Surfactant-free, water-free formable composition and breakable foams and their uses

ABSTRACT

A substantially surface active agent-free and foam adjuvant-free composition which includes a hydrophobic solvent, a wax and a propellant. A substantially surface active agent-free and foam adjuvant-free composition, further comprising, a tetracycline antibiotic, or one or More other active agents. A method of treatment, using a substantially surface active agent-free and substantially foam adjuvant-free composition.

CROSS REFERENCE TO RELATED APPLICATIONS

This is a National Stage application under 35 U.S.C. §371 and claimsbenefit under 35 U.S.C. §119(a) of International Application No.PCT/IB2010/002613 having an International Filing Date of Oct. 1, 2010and entitled “Surfactant-Free, Water-Free, Foamable Compositions andBreakable Foams And Their Uses,” and claims the benefit of priorityunder 35 U.S.C. §119(e) to U.S. Provisional Application No. 61/248,144filed Oct. 2, 2009 and entitled “Surfactant-Free Water-Free FoamableCompositions, Breakable Foams and Their Uses”; U.S. ProvisionalApplication No. 61/322,148 filed Apr. 8, 2010 and entitled“Surfactant-Free Water-Free Foamable Compositions, Breakable Foams andTheir Uses; United States Provisional Application No. 61/349,911 filedMay 31, 2010 and entitled “Surfactant-Free Water-Free FoamableCompositions, Breakable Foams and Their Uses”; U.S. ProvisionalApplication No. 61/385,385 filed Sep. 22, 2010 and entitled“Surfactant-Free Water-Free Foamable Compositions, Breakable Foams andGels and Their Uses”; U.S. Provisional Application No. 61/331,126 filedMay 4, 2010 and entitled “Compositions, Gels and Foams with RheologyModulators and Uses Thereof”; and U.S. Provisional Application No.61/380,568 filed Sep. 7, 2010 and entitled “Surfactant-Free Water-FreeFoamable Compositions and Breakable Foams and Their Uses”; “U.S.Provisional Application No. 61/388,884 filed Oct. 1, 2010 and entitledCompositions, Gels and Foams with Rheology Modulators and Uses Thereof”;all of which are herein incorporated in their entirety by reference.

BACKGROUND

Foam compositions with high amounts of hydrophobic solvents are littleknown in the art.

Foams and, in particular, oleaginous single-phase foams are complicatedsystems which do not form under all circumstances. Slight shifts in foamcomposition, such as by the addition of active ingredients or theremoval of any of the essential ingredients, may destabilize the foam.

The prior art teaches oleaginous foam compositions require significantamounts of surface active agents to form and stabilize a foam. Thesecompositions require various standard surfactants, as essentialcomponents.

Surfactants are known as essential ingredients in foam compositionsbecause of their amphiphilic properties and because they are consideredessential in forming a foam. However, many surfactants are known to beirritating when left on the skin, as they can extract lipids from theskin, thereby damaging skin barrier and exposing the skin to contactwith pro-inflammatory factors. (See for example: Effendy, I. andMaibach, H. I. “Surfactants and Experimental Irritant ContactDermatitis.” Contact Dermatol., 33 (1995), 217-225). Many surfactantscan also react with unstable active agents and lead to their rapiddegradation.

Briefly, the term surfactant has been often loosely used in the art toinclude substances which do not function effectively as stand alonesurfactants to reduce surface tension between two substances or phases.Reduction of surface tension can be significant in foam technology inrelation to the ability to create small stable bubbles. In the contextherein, the term “standard surfactant” or “customary surfactant” refersto customary non-ionic, anionic, cationic, zwitterionic, amphoteric andamphiphilic surfactants. Many standard surfactants are derivatives offatty alcohols or fatty acids, such as ethers or esters formed from suchfatty alcohols or fatty acids with hydrophilic moieties, such aspolyethyleneglycol (PEG). However, a native (non derivatized) fattyalcohol or fatty acid, or wax are not regarded as a standard surfactant.

In the context herein the term “foam adjuvant” includes only fattyalcohols and fatty acids. These are amphiphatic, and essentiallyhydrophobic with a minor hydrophilic region. For the purposes of formingan emulsion these foam adjuvants, unlike “standard” or “customarysurfactants”, are not effective as stand-alone surfactants in foamableemulsion compositions, because of their very weak emulsifying capacityon their own. Fatty alcohols and fatty acids have been loosely describedas co-surfactants in foamable emulsion compositions, because they assistcustomary surfactants to boost foam quality, help evolve the foamingproperties and because they stabilize the foam in part because of theirproperty as thickeners.

SUMMARY

The present application relates to foamable formulations and foams andtheir uses comprising hydrophobic solvents. It further relates tohydrophobic solvents with waxes. In particular it relates to waxes thatare solid at room temperature. In addition, it relates to formulationwith and without an active agent. Surprisingly, the application alsorelates to foamable formulations and foam without surfactants; and orwithout surfactants and foam adjuvants; and or without surfactants andpolymeric agents; and or without surfactants and foam adjuvants andpolymeric agents. In one or more embodiments the hydrophobic solventsare provided as part of a drug carrier. For example certain drugsrequire hydrophobic solvents in order to solubilize them. In one or moreother embodiments, the hydrophobic solvents are provided to facilitateor enhance the transdermal penetration or delivery of a drug. In one ormore additional cases, the formulations are provided to have a waterbarrier effect at a target site, for example where the site of treatmentis a damaged skin and the water barrier effect of hydrophobic solventsis desirable. In some embodiments the formulation may have someocclusivity. In some embodiments petrolatum is added to achieve orenhance an occlusive effect. The present application further relates tocompositions comprising hydrophobic solvents and their uses.

It is known in the art that foams can easily be formulated based on highamounts of water, in combination with surface active agents, foamadjuvants and polymeric agents. As described in the literature,hydrophobic solvents can have a de-foaming effect which makes theformulation of foams based on hydrophobic solvents—challenging. Toovercome this challenge, the prior art requires the use of substantiallevels of surfactants that act as efficient foaming agents. The priorart further teaches the incorporation of foam adjuvants, such as fattyalcohols and fatty acids, as foam boosting agents and also theincorporation of polymeric agents (e.g. gelling agents) as foamstabilizers, which can prolong the collapse time of a foam. Waxes mayalso be introduced into these surfactant based formulations but as willbe appreciated, waxes, which are at ambient temperature can easilyprecipitate. Surface active agents are known to be irritating,especially ionic surface active agents and repeated use can cause dryskin and so it is desirable to reduce their use in pharmaceuticalcompositions intended to treat skin or mucosa. The technical problems tobe overcome in formulating carriers and pharmaceutical compositions withhydrophobic solvent (a) without surfactant; and (b) without surfactantand foam adjuvant; and (c) without polymeric agents and (d) withoutwater are multifold and include finding a suitable substitute forsurfactant which provides foam generating properties; finding a suitablereplacement that preferably does not need to have a foam adjuvantpresent with the surfactant (substitute), which if present would interalia help to boost the foam and as an aid to the surfactant andpreferably does not need to have a polymeric agent present with thesurfactant (substitute), which if present would inter alia help prolongstability of the foam. It was surprisingly discovered in the presentinvention, that surface active agents can be advantageously eliminatedand replaced by waxes in the context of hydrophobic solvent based-foams.Waxes possess several advantages over other foaming agents such asexcellent skin compatibility, almost no chemical reactivity whichensures active ingredients stability and efficient skin occlusion whichhelps reducing skin water loss and can enhance skin penetration ofactive agents. Albeit waxes introduce their own additional problems intoformulating foamable compositions and foams, including their tendency tosolidify and precipitate out from a formulation, and to increasesignificantly the viscosity of an oleaginous composition, and to blockcanister valves, against which the formulations need to be designed sothat the formulations are not negatively disturbed upon adding aneffective amount of propellant and that the formulations are shakableand are homogenous and can readily reform at least upon mild orreasonable shaking prior to use.

In one or more embodiments the drug carrier is formulated for use onsensitive target areas such as sensitive or damages skin areas, wounds,burns, mucosal membranes, body cavities and the eye. In one or moreembodiments the composition is intended for use in treatment orprevention of eye infections.

Unexpectedly, it has been discovered that quality oleaginousformulations and foams can be achieved without the presence ofsignificant amounts of standard surfactants. Also surprisingly it hasbeen discovered that quality oleaginous formulations and foams can beachieved without the presence of significant amounts of foam adjuvants(i.e fatty alcohols and fatty acids) known in the art. Further,unexpectedly, it has been discovered that quality oleaginousformulations and foams can be achieved without the presence ofsignificant amounts of standard polymeric agents (e.g. gelling agents).Thus, in one or more embodiments, there is provided a substantiallysurfactant-free and substantially foam adjuvant-free oleaginousformulation or foam. In one or more preferred embodiments the oleaginousformulations and foams are free of standard surfactants and foamadjuvants. Thus, in one or more embodiments, there is provided asubstantially surfactant free and substantially polymeric agent freeoleaginous formulation or foam. In one or more preferred embodiments theoleaginous formulations and foams are free of standard surfactants andpolymers. Unexpectedly, it has further been discovered that qualityoleaginous formulations and foams can be achieved without the presenceof significant amounts of standard surfactants, foam adjuvants andpolymeric agents known in the art. Thus, in one or more embodiments,there is provided a substantially surfactant free and substantially foamadjuvant free and substantially polymeric agent free oleaginousformulation or foam. In one or more preferred embodiments the oleaginousformulations and foams are free of surface active agents and foamadjuvants and polymeric agents. Moreover, it has been further discoveredthat these formulations and foams can be achieved over a large range ofhydrophobic solvent content. There is thus provided easy to use, stableand non-irritating topical foam formulations, and pharmaceuticalcompositions thereof, containing a stable or stabilized activepharmaceutical or cosmetic agent having a therapeutic or beneficialeffect, intended for treatment of dermal and mucosal tissues free orsubstantially free of standard surface active agents and foam adjuvants.

In one or more embodiments there is provided a safe and effectivefoamable carrier composition and foam comprising a hydrophobic solvent,an oleaginous foaming agent comprising a wax and a liquefied orcompressed gas propellant. In certain embodiments, the concentration ofthe propellant is about 1% to about 30% by weight of the totalcomposition. In other certain embodiments, the concentration of thepropellant is about 3% to about 25% by weight of the total composition;or about 7% to about 17%; or about 10% to about 14%. In additionalembodiments there is provided a safe and effective foamablepharmaceutical or cosmetic composition and foam comprising an effectiveamount of a pharmaceutical or cosmetic active agent, a hydrophobicsolvent, a foaming agent comprising of a wax and a liquefied orcompressed gas propellant. The percent by weight is based on weightfoamable composition; where the ratio of composition other thanpropellant to propellant is from about 100:1 to about 100:30; or fromabout 100:3 to about 100:25; or from about 100:7 to about 100:17; orfrom about 100:10 to about 100:14 The composition does not contain asurfactant or a foam adjuvant; and the foaming effect is achieved by theaddition of the foamer agent, as specified herein. The hydrophobicsolvent is present in a substantial amount. In one or more embodimentsthe hydrophobic solvent is at a concentration between about 40% to about92% or about 50% to about 90% by weight, or about 40% to about 95% byweight or about 70% to about 90% by weight. In alternative embodimentsthe formulation is formulated without propellant and delivered as a gel,ointment or rub. The total weight of the foaming agent which is a wax isabout 8% to about 50% by weight of a wax. In one or more embodiments theamount of wax is less than 55%; or is less than about 54%; or is lessthan about 53%; or is less than about 52%; or is less than about 51%; oris less than about 50% by weight; or is less than about 45%; or is lessthan about 40%; or is less than about 35%; or is less than about 30%; oris less than about 25%; or is less than about 20%; or is less than about15% by weight. In one or more alternative embodiments the formulationcomprises 0% to about 550% wax and about 45% to about 95% hydrophobicsolvent. In certain embodiments the wax is about 1% to about 20% and thehydrophobic solvent is about 75% to about 94%. In certain embodimentsthe wax is about 21% to about 40% and the hydrophobic solvent is about55% to about 74%. In certain embodiments the wax is about 41% to about60% and the hydrophobic solvent is about 35% to about 54%. As will beappreciated from the above illustrative examples as the amount of wax isincreased the amount of hydrophobic solvent is reduced. Accordingly,differing amounts of wax other than the amounts specified can becontemplated with a parallel increase or decrease in solvent asappropriate. In one or more embodiments their total amount (wax plussolvent) is between about 95% and about 100%. In one or more otherembodiments the total amount is between about 92% and about 100%; orbetween about 90% and about 100%; between about 85% and about 100%; orbetween about 90% and about 95%; or between about 90% and about 98% orbetween about 85% and about 95%; or between about 85% and about 98%.

Upon dispensing the foamable carrier composition forms a breakable foamthat is stable, yet breaks easily upon application of shear force. Inone or more embodiments the composition is used for intradermal deliveryof the active agent into the skin with minimal or negligible transdermaldelivery. In one or more alternative embodiments a formulation isprovided to achieve intra mucosal delivery. In certain embodiments thecomposition provides for transdermal delivery. In one or moreembodiments the composition can be used for prevention of a disease ordisorder. The composition or foam is applied to a target surface or areain or on which prevention is sought. In other embodiments thecomposition or foam is used to treat or ameliorate a disease ordisorder. In still further embodiments it may be used to provide aperiod of remission from the disease or disorder.

According to an embodiment the one or more active agents is selectedfrom the group consisting of adipic acid, an acaricide, an active herbalextract, an age spot and keratose removing agent, an allergen, an alphahydroxyl acid, an analgesic agent, an androgen, an anesthetic, an antiwrinkle agent, an antiacne agent, an antiaging agent, an antiallergicagent, an antiandrogen agent, an antiapoptotic agent, an antibacterialagent, an antibiotic, an antibiotic agent, an antiburn agent, ananticancer agent, an antidandruff agent, an antidepressant, anantidermatitis agent, an antiedemic anent, an antifungal agent, anantihelminth agent, an antihistamine, an anti-hyperkeratosis agent, ananti-infective agent, an antiinflammatory agent, an antiirritant, anantilipemic agent, an antimicrobial agent, an antimycotic agent, anantioxidant, an antiparasitic agent, an anti-photoaging agent, ananti-photodamaging agent, an antiproliferative agent, an antipruriticagent, an antipsoriatic agent, an antirosacea agent, an antiseborrheicagent, an antiseptic agent, an antiswelling agent, an antiviral agent,an anti-wart agent, an anti-wrinkle agent, an anti-yeast agent, anastringent, azelaic acid, benzoyl chloride, benzoyl peroxide, abeta-hydroxy acid, calcitriol, calcium hypochlorite, carbon, acardiovascular agent, a chemotherapeutic agent, a corticosteroid, adicarboxylic acid, a dihydrotestosterone inhibitor, a disinfectant,doxycycline, an estrogen, a fungicide, fumaric acid, glycolic acid, ahair growth regulator, a haptene, a herbal extract (comprising an activesubstance), a hormonal agent, a hormone, a hydroxy acid, an immunogenicsubstance, an immunomodulator, an immunoregulating agent, animmunostimulant, an immunosuppressant, an immunosuppressive agent, aninsect repellent, an insecticide, iron oxide, a keratolytic agent,lactic acid, a lactam, lidocaine, a local anesthetic agent, alubricating agent, a masking agent, a metal, a metal oxide, minocycline,a mitocide, mometasone fuorate, a neuropeptide, a non-steroidalanti-inflammatory agent, an organo-beryllium compound, anorgano-metallic compound, an oxidizing agent, and organo-boron compound,a pediculicide, a peptide, a pesticide, a photodynamic therapy agent, aprogesterone, a prostaglandin, a protein, a radical scavenger, arefatting agent, a retinoid, a sedative agent, a scabicide, sebacicacid, a sedative, a sedative agent, a self tanning agent, siliconeoxide, silver, a silver compound, a skin protective agent, a skinwhitening agent, a steroid, a steroid hormone, a steroidalanti-inflammatory agent, talc, titanium dioxide, a tellurium compound, atestosterone inhibitor, a tetracycline antibiotic, urea, a ureaderivative, a vasoactive agent, a vasoconstrictor, a vasodilator, avitamin, a vitamin A, a vitamin A derivative, a vitamin B, a vitamin Bderivative, a vitamin C, a vitamin C derivative, a vitamin D, a vitaminD analog, a vitamin D derivative, a vitamin E, a vitamin E derivative, avitamin F, a vitamin F derivative, a vitamin K, a vitamin K derivative,a wart remover, a wound healing agent, zinc oxide, zirconium oxide.According to a further embodiment the active agent is a tetracyclineantibiotic. In certain embodiments the tetracycline is minocycline. Incertain embodiments the tetracycline is doxycycline. In certainembodiments the active agent is selected from a group consisting ofcalcitriol, mometasone fuorate, calcitriol and lidocaine. According to afurther embodiment the active agent is chemically stable for at leasttwo months and where the active agent is compatible with the otheringredients. According to a further embodiment the active agent ischemically stable for at least six months; or for at least nine monthsfor at least twelve months; or for at least fifteen months; or for atleast eighteen months; or for at least twenty one months; or for atleast twenty four months.

As is known to one skilled in the art, in some instances a specificactive agent may have more than one activity, function or effect.

In certain embodiments, the inclusion of two or more therapeutic agentsin the foamable pharmaceutical composition is desirable.

In one or more embodiments the foamable composition further comprises afatty alcohol. In one or more embodiments the fatty alcohol is atherapeutically active fatty alcohol. The fatty alcohol can be astraight chain fatty alcohol, a saturated fatty alcohol, an unsaturatedfatty alcohol, a hydroxyl substituted fatty alcohol or a branched fattyalcohol.

In an embodiment, the foamable composition further comprises a fattyacid. The fatty acid can be a straight chain fatty acid, a saturatedfatty acid, an unsaturated fatty acid, a hydroxyl fatty acid or abranched fatty acid. In an embodiment the fatty acid is atherapeutically active fatty acid.

In an embodiment, the foamable composition comprises a foaming agentwhich is a wax. The wax can be a liquid wax, a solid wax, an animal wax,a vegetable wax, a mineral wax, a natural wax or a synthetic wax. In anembodiment the wax is selected from a list comprising paraffin wax,beeswax, hydrogenated castor oil or mixtures thereof. In one or moreembodiments there is provided a composition comprising a paraffin wax.In one or more embodiments the paraffin wax can have a melting pointform about 37° C. In one or more embodiments the paraffin wax comprisesof alkane chains of between about C₂₀H₄₂ to C₄₀H₈₂. In one or moreembodiments the alkane chains are substantially straight chain. In someembodiments branched or unsaturated molecules can be present. Branchedchains are sometimes referred to as isoparaffins. In one or moreembodiments the paraffin wax can be selected from the group consistingof paraffin wax 58-62° C., paraffin wax 51-53° C., and paraffin wax42-44° C., or mixtures thereof. In one or more other embodiments othermelting point ranges can be selected such as 125° F. to 135° F.; 127° F.to 130° F.; 130° F. to 135° F.; 135° F. to 145° F.; 140° F. to 145° F.;150° F. to 155° F.; 150° F. to 165° F.; 160° F. to 165° F.; or such as43-46° C.; 46-53° C.; 48-50° C.; 52-54° C.; 53-55° C.; 54-57° C.; 54-58°C.; 58-60° C.; 59-61° C.; 60-62° C.; 62-66° C.; 65-68° C.; or any othersimilar or relative range(s) or mixtures thereof. In an embodiment thewax is fully refined. In an embodiment it is suitable for cosmetic use.In an embodiment it is suitable for pharmaceutical use. In an embodimentthe paraffin wax is soft.

In one or more embodiments the drug carrier is formulated substantiallyfree of short chain alcohols, such as, ethanol, propanol or butanol. Inone or more embodiments the drug carrier is formulated essentially freeof short chain alcohols. In one or more specific embodiments the drugcarrier is formulated essentially free of fatty alcohols and or fattyacids. In one or more other specific embodiments the drug carrier isformulated essentially free of polyols. In one or more other specificembodiments the drug carrier is formulated essentially free ofsurfactants and or short chain alcohols and or polyols and or fattyacids and or fatty alcohols. In one or more other specific embodimentsthe drug carrier is formulated substantially free of surfactants and orshort chain alcohols and or polyols and or fatty acids and or fattyalcohols.

In one or more embodiments there is provided a composition which isessentially waterless. In one or more embodiments there is provided acomposition which is surfactant free. In one or more embodiments thereis provided a surfactant free composition that is also foam adjuvantfree, and or polymer free. In one or more embodiments there is provideda surfactant free composition that is also free of short chain alcoholsand or polyol-free.

In one or more embodiments there is provided a composition comprising apropellant having a vapor pressure between about 10 psi and about 130psi. In one or more embodiments there is provided a compositioncomprising a propellant which is hydrocarbon propellant or ahydrofluorocarbon or another environmentally acceptable propellant.

In one or more embodiments there is provided a single phase composition.

In one or more embodiments there is provided a composition comprising ahydrophobic solvent which is a liquid oil, selected from the groupconsisting of hydrocarbon oils, mineral oil, liquid paraffin,isoparaffin, polyalphaolefin, polyolefin, polyisobutylene, syntheticisoalkane, isohexadecane isododecane, ester oils, alkyl benzoate, alkyloctanoate, C12-C15 alkyl benzoate, C12-C15 alkyl octanoate, arachidylbehenate, arachidyl propionate, benzyl laurate, benzyl myristate, benzylpalmitate, bis(octyldodecyl stearoyl) dimer dilinoleate, butylmyristate, butyl stearate, cetearyl ethylhexanoate, cetearylisononanoate, cetyl acetate, cetyl ethylhexanoate, cetyl lactate, cetylmyristate, cetyl octanoate, cetyl palmitate, cetyl ricinoleate, decyloleate, diethyleneglycol diethylhexanoate, diethyleneglycol dioctanoate,diethyleneglycol diisononanoate, diethyleneglycol diisononanoate,diethylhexanoate, diethylhexyl adipate, diethylhexyl malate,diethylhexyl succinate, diisopropyl adipate, diisopropyl dimerate,diisopropyl sebacate, diisosteary dimer dilinoleate, diisostearylfumerate, dioctyl malate, dioctyl sebacate, dodecyl oleate, ethylhexylpalmitate, ester derivatives of lanolic acid, ethylhexyl cocoate,ethylhexyl ethylhexanoate, ethylhexyl hydroxystarate, ethylhexylisononanoate, ethylhexyl palmytate, ethylhexyl pelargonate, ethylhexylstearate, hexadecyl stearate, hexyl laurate, isoamyl laurate, isocetylisocetyl behenate, isocetyl lanolate, isocetyl palmitate, isocetylstearate, isocetyl salicylate, isocetyl stearate, isocetyl stearoylstearate, isocetearyl octanoate, isodecyl ethylhexanoate, isodecylisononanoate, isodecyl oleate, isononyl isononanoate, isodecyl oleate,isohexyl decanoate, isononyl octanoate, isopropyl isostearate, isopropyllanolate, isopropyl laurate, isopropyl myristate, isopropyl palmitate,isopropyl stearate, isostearyl behenate, isosteary citrate, isostearylerucate, isostearyl glycolate, isostearyl isononanoate, isostearylisostearate, isostearyl lactate, isostearyl linoleate, isostearyllinolenate, isostearyl malate, isostearyl neopentanoate, isostearylpalmitate, isosteary salicylate, isosteary tartarate, isotridecylisononanoate, isotridecyl isononanoate, lauryl lactate, myristyllactate, myristyl myristate, myristyl neopentanoate, myristylpropionate, octyldodecyl myristate, neopentylglycol dicaprate, octyldodecanol, octyl stearate, octyl palmitate, octyldodecyl behenate,octyldodecyl hydroxystearate, octyldodecyl myristate, octyldodecylstearoyl stearate, oleyl erucate, oleyl lactate, oleyl oleate, propylmyristate, propylene glycol myristyl ether acetate, propylene glycoldicaprate, propylene glycol dicaprylate, propylene glycol dicaprylate,maleated soybean oil, stearyl caprate, stearyl heptanoate, stearylpropionate, tocopheryl acetate, tocopheryl linoleate, glyceryl oleate,tridecyl ethylhexanoate, tridecyl isononanoate and triisocetyl citrate,liquid triglycerides, oils of plant origin, alexandria laurel tree oil,avocado oil, apricot stone oil, barley oil, borage seed oil, calendulaoil, canelle nut tree oil, canola oil, caprylic/capric triglyceridecastor oil, coconut oil, corn oil, cotton oil, cottonseed oil, eveningprimrose oil, flaxseed oil, groundnut oil, hazelnut oil, glycerethtriacetate, glycerol triheptanoate, glyceryl trioctanoate, glyceryltriundecanoate, hempseed oil, jojoba oil, lucerne oil, maize germ oil,marrow oil, millet oil, neopentylglycol dicaprylate/dicaprate, oliveoil, palm oil, passionflower oil, pentaerythrityl tetrastearate, poppyoil, propylene glycol ricinoleate, rapeseed oil, rye oil, safflower oil,sesame oil, shea butter, soya oil, soybean oil, sweet almond oil,sunflower oil, sysymbrium oil, syzigium aromaticum oil, tea tree oil,walnut oil, wheat germ glycerides and wheat germ oil, an essential oil,PPG alkyl ethers, PPG-2 butyl ether, PPG-4 butyl ether, PPG-5 butylether, PPG-9 butyl ether, PPG-12 butyl ether, PPG-14 butyl ether, PPG-15butyl ether, PPG-15 stearyl ether, PPG-16 butyl ether, PPG-17 butylether, PPG-18 butyl ether, PPG-20 butyl ether, PPG-22 butyl ether,PPG-24 butyl ether, PPG-26 butyl ether, PPG-30 butyl ether, PPG-33 butylether, PPG-40 butyl ether, PPG-52 butyl ether, PPG-53 butyl ether,PPG-10 cetyl ether, PPG-28 cetyl ether, PPG-30 cetyl ether, PPG-50 cetylether, PPG-30 isocetyl ether, PPG-4 lauryl ether, PPG-7 lauryl ether,PPG-2 methyl ether, PPG-3 methyl ether, PPG-3 myristyl ether, PPG-4myristyl ether, PPG-10 oleyl ether, PPG-20 oleyl ether, PPG-23 oleylether, PPG-30 oleyl ether, PPG-37 oleyl ether, PPG-40 butyl ether,PPG-50 oleyl ether and PPG-11 stearyl ether. Preferred PPG alky ethersaccording to the present invention include PPG-15 stearyl ether, PPG-2butyl ether and PPG-9-13 butyl ether, oils from animal origin, herringoil, cod-liver oil and salmon oil, a therapeutic oil, manuka oil,rosehip oil, tea tree oil, basil oil, camphor oil, cardamom oil, carrotoil, citronella oil, clary sage oil, clove oil, cypress oil,frankincense oil, ginger oil, grapefruit oil, hyssop oil, jasmine oil,lavender oil, lemon oil, mandarin oil, marjoram oil, myrrh oil, nerolioil, nutmeg oil, petitgrain oil, sage oil, tangerine oil, vanilla oilverbena oil, silicone oils, cyclomethicone, dimethicone, polyalkylsiloxane, polyaryl siloxane, polyalkylaryl siloxane, polyether siloxanecopolymer, poly(dimethylsiloxane)-(diphenyl-siloxane) copolymer,dimethyl polysiloxane, epoxy-modified silicone oil, fatty acid-modifiedsilicone oil, fluoro group-modified silicone oil,methylphenylpolysiloxane, phenyl trimethicone, polyether group-modifiedsilicone oil cyclomethicone, cyclotetrasiloxane, cyclohexasiloxane,phyenyltrimethicone, Dow corning 246 Fluid (d6+d5) (cyclohexasiloxane &cyclopentasiloxane), Dow Corning 244 Fluid (cyclotetrasiloxane),Cyclomethicone 5-NF (cyclopentasiloxane), stearyl dimethicone,phenyltrimethicone, cetyl dimethicone, caprylyl methicone, PEG/PPG 18/18dimethicone, or dimethiconol, capric/caprylic triglycerides,cyclomethicone; isopropyl myristate, isopropyl palmitate, PPG-15 stearylether; octyldodecanol; isohexadecanol, diisopropyl adipate; cetearyloctanoate; MCT oil; heavy mineral oil; light mineral oil; coconut oiland soybean oil, an unsaturated or polyunsaturated oil, a diglyceride, aPPG alkyl ether or mixtures thereof.

According to additional embodiments there is provided a method ofproducing a foamable composition, including:

-   -   1. providing a foamable therapeutic composition including a        therapeutic agent at a therapeutically effective concentration,        a hydrophobic solvent, for example, at a concentration of about        50% to about 90% by weight and a foaming agent including a wax;    -   2. introducing the foamable composition in an aerosol packaging        assembly, comprising of a container, suitable for containing a        pressurized product and a valve, capable of extruding a foam;        and    -   3. introducing to the aerosol packaging assembly a liquefied or        compressed gas propellant at a concentration.

According to additional embodiments the formulation comprises about 1%to about 18% wax and about 80% to about 94% hydrophobic solvent. Infurther embodiments wax may be in excess of 18%.

In one or more embodiments there is provided a method of preventing ortreating or alleviating a dermatological or mucosal disorder,comprising: applying a substantially surfactant free foamablecomposition to a surface having or anticipated to have a dermatologicalor mucosal disorder or disease in need of treatment. In one or moreembodiments the active agent is a placebo.

In one or more embodiments there is provided use of a substantiallysurfactant free foamable composition for preventing or treating oralleviating a dermatological or mucosal disorder.

In one or more embodiments the disorder is selected form the groupconsisting of abscess, acne, acne conglobata, acne fulminans, acnevulgaris, acne scars, acute febrile neutrophilic dermatosis, acutelymphangitis, allergic contact dermatitis, alopecia, athlete's foot,atopic dermatitis, bacterial skin infections, baldness, basal cellcarcinoma, blisters, bromhidrosis, bullous pemphigoid, burn, callusescandidiasis, carbuncles, cellulitis, chemical burns, chicken pox,cholesteatoma, cholinergic urticaria, chronic effects of sunlight, coldsores, cold urticaria, comedones, corns, creeping eruption, cutaneousabscess, cutaneous larva migrans, cutaneous myiasis, dark spots,delusional parasitosis, Dercum disease, dermatitis, dermatitisherpetiformis, dermatological pain, dermatological inflammation,dermographism, dermatophytoses, drug eruptions and reactions,dyshidrotic eczema, ectodermal dysplasia, eczema, eethyma, epidermoidcyst, epidermal necrolysis, erysipelas, erysipelas, erythrasma,exfoliative dermatitis, erythema multiforme, erythema nodosum,folliculitis, fungal nail infections, fungal skin infections, furuncles,gangrene, genital herpes, granuloma annulare, head lice, hidradenitissuppurativa, hives, folliculitis, hirsutism, hyperhidrosis,hypohidrosis, ichthyosis, impetigo, inflammatory acne, ingrown nails,intertrigo, irritant contact dermatitis, ischemic necrosis, itching,jock itch, Kaposi's sarcoma, keratosis pilaris, lichen simplexchronicus, lichen planus, lichen sclerosus, lymphadenitis,lymphadenitis, lymphangitis, malignant melanoma, mastocytosis, measles,melanoma, melanoma, miliaria, moles, molluscum contagiosum, MRSA,necrotizing subcutaneous infection, necrotizing fasciitis, necrotizingmyositis, nodular papulopustular acne, non-inflammatory acne, nummulardermatitis, oral herpes, panniculitis, parapsoriasis paronychia,parasitic skin infections, pemphigus, photo-allergy, photo-damage,photo-irritation, photosensitivity, papules, pediculosis, perioraldermatitis, pimples, pityriasis rosea, pityriasis Lichenoides,pityriasis rosea, pityriasis rubra pilaris, poison ivy, poison oakpost-operative or post-surgical skin conditions, pressure ulcers,pressure urticaria, pruritis, pseudofolliculitis barbae, psoriasis,PUPPP, purpura, pustules, pyogenic granuloma, rash, ringworm, rosacea,roseola, rubella, scabies, scalded skin syndrome, scarring, scleroderma,sebaceous cyst, seborrheic dermatitis, seborrheic keratosis, shingles,skin aging, skin cancer, skin neoplasia, skin neoplasms, skin rash, skinulcers, squamous cell carcinoma, staphylococcal scalded skin syndrome,stasis dermatitis, Stevens-Johnson syndrome, sunburn, sun spots, thermalburns, tinea corporis, tinea cruris, tinea pedis, tinea versicolor,toxic epidermal necrolysis, trauma or injury to the skin, varicellazoster virus, vitamin D deficiency, viral skin infections, vitiligo,warts, water hives, wrinkles, xerosis, yeast skin infections and zoster.

According to further embodiments there is provided a method ofpreventing, treating ameliorating or eliminating a disorder by selectingand releasing on to a convenient surface a safe and effectivepharmaceutical or cosmetic foamable composition comprising an effectiveamount of a pharmaceutical or cosmetic agent, a hydrophobic solvent, afoaming agent comprising a wax and a liquefied or compressed gaspropellant at a concentration of about 1% to about 30% by weight of thetotal composition; directing the released foam on to a target on apatient in need or anticipated need; applying a shear force to andspreading the foam over the target surface such that after a simple rubthe foam is no longer visible to the naked eye as it is absorbed rapidlyon to the target surface.

According to one of more further embodiments the disorder treated by thefoamable composition is selected from the group consisting of adermatose, a dermatitis, a vaginal disorder, a vulvar disorder, an analdisorder, a disorder of a body cavity, an ear disorder, a disorder ofthe nose, a disorder of the respiratory system, a bacterial infection, afungal infection, a viral infection, dermatosis, dermatitis, parasiticinfections, disorders of hair follicles and sebaceous glands, scalingpapular diseases, benign tumors, malignant tumors, reactions tosunlight, bullous diseases, pigmentation disorders, disorders ofcornification, pressure sores, disorders of sweating, inflammatoryreactions, xerosis, ichthyosis, an allergy, a burn, a wound, a cut, achlamydia infection, a gonorrhea infection, hepatitis B, herpes,HIV/AIDS, human papillomavirus (HPV), genital warts, bacterialvaginosis, candidiasis, chancroid, granuloma Inguinale, lymphogranlomavenereum, mucopurulent cervicitis (MPC), molluscum contagiosum,nongonococcal urethritis (NGU), trichomoniasis, vulvar disorders,vulvodynia, vulvar pain, a yeast infection, vulvar dystrophy, vulvarintraepithelial neoplasia (VIN), contact dermatitis, osteoarthritis,joint pain, an hormonal disorder, a pelvic inflammation, endometritis,salpingitis, oophoritis, genital cancer, cancer of the cervix, cancer ofthe vulva, cancer of the vagina, vaginal dryness, dyspareunia, an analand rectal disease, an anal abscess/fistula, anal cancer, an analfissure, an anal wart, Crohn's disease, hemorrhoids, anal itch, pruritusani, fecal incontinence, constipation, polyps of the colon and rectum.

DETAILED DESCRIPTION Foamable Composition and Foam Properties

The ability to achieve quality foam with a substantial concentration ofhydrophobic solvent without a surfactant and without a foam adjuvant andwithout a polymer is surprising, because usually, such solvents are notprone to creating a foam. The challenge is not just to achieve a qualityfoam but also to attain a formulation that will satisfy a plurality oftwo, three, four, five, six or more of the following propertyspecifications simultaneously.

Notably, the pressurized composition is flowable and releases a foamfreely, even though it might be expected that such concentrations of waxwould make the hydrophobic solvent very viscous or ‘semi-solid’.

-   -   1. Uniformity: The composition should be formulated so that it        is and can remain uniform upon shaking and that it can        reconstitute upon shaking without phase separation or        precipitation over a reasonable time. This property is of        importance when the product is intended to be a pharmaceutical        product.    -   2. Flowability: The composition, when placed in an aerosol        container and pressurized with a propellant should be flowable        such that it can be expelled through the canister valve. It        should preferably also be shakable inside the container. These        requirements create a formulation challenge, because non-viscous        flowable and shakable compositions are prone to undergo phase        separation or precipitation.    -   3. Quality: Upon release from the can, the composition should        generate a foam of good or excellent quality having low density        and small bubble size.    -   4. Stability/Breakability: The fine balance between stability        and breakability of the foam coming out of the container is very        delicate: on one hand the foam should preferable not be “quick        breaking”, i.e., it should be at least short term stable upon        release from the pressurized container and not break as a result        of exposure to skin temperature; and on the other hand, it        should be “breakable”, i.e., it should spread easily, break down        and absorb into the skin or membrane upon application of mild        shear force.    -   5. Skin Feeling: To ensure patient compliance the skin feeling        after application should be pleasant, and greasy or waxy        residues should be minimal.    -   6. Non-irritating: The above requirements should be achieved        with the awareness that formulation excipients, especially        surfactants, can be irritating, and should preferably be        eliminated from the composition or reduced as much as possible.    -   7. Delivery: Finally, the composition should also be designed to        ensure efficient delivery of a therapeutic agent into the target        site of treatment.    -   8. Compatibility: The components of the composition should be        compatible and not react with an active agent.

Based on extensive investigations and trial and error experiments, ithas been found that such properties can be achieved for formulations asdescribed below and which are further advantageous because of theability of hydrophobic solvents to dissolve or suspend certain activeagents while providing an environment for the active agent which assistsin preventing their degradation.

Compositions

All % values are provided on a weight (w/w) basis.

In one or more embodiments there is provided a foamable carriercomposition including:

-   -   1. a hydrophobic solvent    -   2. a foaming agent comprising a wax;    -   3. a liquefied or compressed gas propellant.        Waxes

In one or more embodiments the wax includes a paraffin wax. In one ormore embodiments the paraffin wax includes a paraffin wax having amelting point or melting point range somewhere in between about 47° C.to about 64° C. In one or more embodiments the paraffin wax includes aparaffin wax having a melting point of about 58° C. to 62° C. In one ormore embodiments the paraffin wax includes a paraffin wax having amelting point of about 51° C. to 53° C. In one or more embodiments theparaffin wax includes a paraffin wax having a melting point of about 42°C. to 44° C. In one or more embodiments the wax includes a beeswax. Inone or more embodiments the wax includes a hydrogenated caster oil,which is a wax.

Paraffin waxes are primarily mixtures of solid saturated hydrocarbonshaving the general formula CnH(2n+2).

Unexpectedly it was found that paraffin waxes could form quality foamwith oils without the assistance of surfactants, and/or foam adjuvantsand/or polymers. Without being bound to a specific theory, the abilityof paraffin wax to facilitate the formation of quality stable breakablefoam with oils appears to relate to its unique molecular structure andsize and resultant Van der Waals forces. Paraffin waxes are comprisedprimarily of long straight chain molecules having chains consisting ofbetween about 20 to about 40 carbons. Higher melting point paraffinwaxes will be expected to have a higher proportion of longer chains thanlower melting waxes. Introduction of branched chains may result in areduction of melting point. Without being bound to a specific theory,such long hydrocarbon chains exhibit momentary asymmetry in the electrondistribution resulting in temporary dipoles that induce similar dipolesin nearby molecules (Van der Waals forces). This phenomenon isespecially prevalent in long molecules like paraffin wax, and less so inthe shorter (but otherwise similar) mineral oil.

Apparently, the temporary dipole (+)------(−) in one molecule induces adipole in the opposite direction (−)--------(+) in another molecule.This interaction occurs between the paraffin wax and other compoundswithin the composition. Thus, it may be concluded that molecular rangeswithin about C20-C40 have preferred capabilities in terms of stablebreakable foam formation.

There seems to be another coinciding property of paraffin wax that maybe involved with foam stability, which is its critical surface tension(“CST”). Hydrophobic behavior of surfaces is generally considered tooccur when CST is less than 35 mN/m. At first, the decrease in criticalsurface tension is associated with oleophilic behavior, i.e. the wettingof the surfaces by hydrocarbon oils.

Paraffin wax is unique among other hydrocarbon chains by having a CST ofabout 25 (e.g., 25.5), which is about in the middle of the hydrophobicrange. Thus, paraffin waxes are somewhat amphipatic which may alsocontribute to foam stability. Notably, in comparison to longerhydrocarbons, such as polyethylene and polypropylene, paraffin wax ismuch more hydrophobic, thereby decreasing the surface tension of thehydrophobic solvents in the composition and facilitating foam formationand stabilization (the CST of polypropylene 31.0 and polyethylene 33.0).

The chain length amongst other things is responsible for the differentmelting points of the paraffin waxes. It was found that higher meltingpoint paraffin waxes could form quality foams with less material thanlower melting point fractions. Without being bound by any theory, it maybe postulated that since high melting point fractions have longerchains, the Van der Vaals forces are greater so lower amounts canfacilitate the formation of quality short term thermally stable foams.Thus, in an embodiment of the present invention, there is provided aparaffin wax, having CST of about 25; or between about 20 to about 30;or about 22 to about 28; about 23 to about 27; about 20 to about 30. Inan embodiment selecting the CST of a wax is a means of providing afoamable formulation with a hydrophobic solvent that will generate afoam of quality that is at least short term stable.

Hydrogenated castor oil consists mainly of triglycerides ofhydroxystearic acid and is a solid wax.

Beeswax contains, for example, a high proportion of wax esters (about 35to 80%), which are linear monoesters of straight-chain fatty alcoholswith even-numbered carbon chains from C24 to C36 esterified withstraight-chain fatty acids such as 16:0 and 18:0 fatty acids some withhydroxyl groups in the ω-2 and ω-3 positions. The wax esters can consistof C40 to C46 molecular species, Also present are free acids (about 14%)and carbohydrates (about 12%) as well as approximately 1% free waxalcohols and stearic esters of fatty acids.

In one or more embodiments, the wax is a polyolefin such aspolyethylene, polypropylene, polymethylpentene, polybutene, a polyolefinelastomer, polyisobutylene, ethylene propylene rubber, ethylenepropylene diene Monomer (M-class) rubber, polyethylene terephthalate,polydicyclopentadiene, linear polyolefins, branched polyolefins, cyclicpolyolefins, low density polyolefins, high density polyolefins,polyolefins with a low molecular weight, polyolefins with a highmolecular weight, halogenated polyolefins and the like and mixturethereof.

In one or more embodiments, the wax is polyvinyl chloride,polyvinylidene chloride, polyvinylidene fluoride, polyvinyl fluoride,polytetrafluoro ethylene, polychlorotrifluoro ethylene, polystyrene,polybutadiene, polyisoprene, polychloroprene, polymethylpentene and thelike and mixture thereof.

In one or more certain embodiments a fatty alcohol and or a fatty acidmay be added to the wax.

In one or more embodiments oily emollients are added to provide orimprove a pleasant skin feeling, and or lubricating effect with reducedfriction. In one or more embodiments volatile silicones are added toreduce greasy feeling. In one or more embodiments various waxes areadded to improve rheology or stabilize foam structure.

Surfactants play a role in foam formation and induce foam stability. Inone or more embodiments the formulation is substantially or essentiallyfree of surfactants. In one or more embodiments a small amount ofsurfactant may be added, preferably less than 1%. Scientific literatureis not always accurate and may loosely or even inaccurately describe asubstance as a surfactant. For example, fatty alcohols or fatty acids(in the absence of a base) when used in combination with classicsurfactants have sometimes been referred to as surfactants, whereas atbest they merely function as an aid to classic surfactant and mayloosely be termed as a co-surfactant but they are not able to stabilizean emulsion and achieve a stable foam emulsion on their own without thepresence of a true surfactant. (For more detail see “co-surfactant”below.) In the context of the present application such fatty acids andfatty alcohols are not surface active agents but are foam adjuvants.Similarly propoxylated lanolin oil derivatives have been looselyreferred to as surfactants. In the context herein they are emollients(not surfactants). In one or more embodiments the composition issubstantially free of foam adjuvants and comprises less than about 5%final concentration of foam adjuvants, preferably less than 2%, morepreferably less than 1%. Where a formulation includes insignificantamounts of foam adjuvants it is considered to be essentially free ofthem. In one or more embodiments the composition is essentially free offoam adjuvants such as fatty alcohols and or fatty acids. In one or moreembodiments a small amount of foam adjuvant may be added, preferablyless than 1%. In one or more embodiments the composition is essentiallyfree of propoxylated lanolin oil derivatives. In one or more embodimentsthe composition is essentially free of ethoxylated lanolin oilderivatives. In further embodiments the compositions are free of suchderivatives. In one or more certain embodiments the composition is freeof PPG, lanolin oils, such as PPG 40 PEG 60 lanolin oil. In one or moreembodiments foam adjuvants (i.e. fatty alcohols and fatty acids) andadditives (such as SiO2 which acts as a thickener and can providethixotropy) can be added to improve rheology or stabilize foam structureor as a protective agent. In one or more embodiments antioxidants can beused to prevent degradation/oxidation, for example, butylatedhydroxytoluene, which is a fat soluble antioxidant.

In one or more embodiments the foamable composition is substantiallysurfactant and foam adjuvant free. In one or more other embodiments itis essentially free of any surfactants and foam adjuvants.

Upon release from an aerosol container, the foamable composition formsan expanded breakable foam suitable for topical administration.

The foamable composition is suitable for administration to various bodyareas, including, but not limited to the skin, a body surface, a bodycavity, a mucosal surface, e.g., the mucosa of the nose, mouth and eye,the ear, the respiratory system, the vagina or the rectum (severally andinterchangeably termed herein “target site”).

In one or more embodiments, the composition is waterless. By waterlessis meant that the composition contains no or substantially no, free orunassociated or absorbed water. It will be understood by a person of theart that to the extent the waterless solvents and substances misciblewithin them of the present disclosure are hydrophilic, they can containwater in an associated or unfree or absorbed form and may absorb waterfrom the atmosphere.

According to one or more embodiments, the foamable composition furthercomprises one or more cosmetic active agents or a pharmaceutical activeagents (severally and interchangeably termed herein “active agent”).

In one or more embodiments the carrier comprises an active agent whichdegrades in the presence of water, and in such cases the presence ofwater in the composition is clearly not desirable. Thus, in certainpreferred embodiments, the composition is waterless. In otherembodiments the active agent may tolerate the presence of a small amountof water and the waterless composition is substantially non-aqueous. Theterm “substantially non-aqueous” is intended to indicate that thewaterless composition has water content preferably below about 2%, suchas, below about 1.5%, below about 1%; or below about 0.5%. In certainembodiments the amount of water is about or less than about 5%. Wherewater is present the formulation may be an emulsion or may form micellesor a colloid.

In one or more embodiments there is provided a foamable therapeuticcomposition including:

-   -   1. an active agent;    -   2. a hydrophobic solvent between about 40% to about 92% by        weight;    -   3. a foaming agent comprising between about 8% to about 50% by        weight of wax;    -   4. a liquefied or compressed gas propellant wherein the percent        by weight is based on weight foamable composition; wherein the        ratio of composition other than propellant to propellant is from        about 100:3 to about 100:30; and    -   wherein upon dispensing the foamable carrier composition forms a        breakable foam that is stable, yet breaks easily upon        application of shear force.

In one or more embodiments the hydrophobic solvent range is betweenabout 35% to about 95%; about 40% to about 95%; about 40% to about 92%;about 45% to about 92%; about 50% to about 92%; about 55% to about 92%;about 60% to about 92%; about 40% to about 90%; about 45% to about 90%;about 50% to about 90%; about 55% to about 90%; about 60% to about 90%;about 40% to about 85%; about 45% to about 85%; about 50% to about 85%;about 55% to about 85%; about 60% to about 85% about 40% to about 80%;about 45% to about 80%; about 50% to about 80%; about 55% to about 80%;about 60% to about 80%; about 40% to about 70%; about 45% to about 70%;about 50% to about 70%; about 55% to about 70%; or about 60% to about70%

In one or more embodiments the wax range is between about 5% to about52%; about 8% to about 52%; about 10% to about 52%; about 15% to about52%; about 20% to about 52%; about 25% to about 52%; about 30% to about52%; 5% to about 50%; about 8% to about 50%; about 10% to about 50%;about 15% to about 50%; about 20% to about 50%; about 25% to about 50%;about 30% to about 50%; 5% to about 45%; about 8% to about 45%; about10% to about 45%; about 15% to about 45%; about 20% to about 45%; about25% to about 45%; or about 30% to about 45%; 5% to about 40%; about 8%to about 40%; about 10% to about 40%; about 15% to about 40%; about 20%to about 40%; about 25% to about 40%; or about 30% to about 40%;

In one or more embodiments, at least a portion of the therapeutic agentis suspended. In one or more embodiments the therapeutic agent isdissolved. In one or more embodiments it is partly suspended and partlydissolved. In one or more embodiments the suspended agent is evenly orhomogenously distributed throughout the composition. In one or moreembodiments homogeneity is achieved after shaking shortly beforeintended use.

Formulations containing high amounts of hydrophobic solvents (such asmineral oil) are not prone to foaming. For example, it has been foundthat a formulation containing only mineral oil and propellants did notproduce foam. Similarly, formulations containing paraffin wax andpropellant only did not produce foam. It has also been found that when apropellant is added to combinations of one or more different oils withrelatively low levels of one or more different waxes in the absence offoam stabilizers such as surfactants or foam adjuvants, foams weremostly not produced at all or were not of quality and collapsed rapidly.In other words they were not short term stable and breakable qualityfoams.

Surprisingly, when propellant was added to formulations containing acombination of certain hydrophobic solvents and waxes, preferablyparafin wax, together having a total weight of about 100% or about 95%,short term stable yet breakable quality foams were successfully producedin the absence of customary surfactants and in the absence of customaryfoam adjuvants. Thus, unexpectedly it was discovered that wax hasfoaming or foam boosting properties of its own when formulated withhydrophobic solvents, such as mineral oil, and provides breakable shortstable foams of good quality. The amount of wax required depends on thetype of wax selected. In general, the amounts of parafin waxes having ahigher melting point range needed to achieve a good quality foam can beless than the amounts of parafin waxes having a lower melting pointrange. Moreover, in general, higher amounts of hydrogenated caster oilwax or beeswax are needed to achieve a foam compared to parafin wax.Similarly, higher amounts of beeswax are needed to achieve a foamcompared to hydrogenated caster oil wax

For example, formulations containing between about 50% and about 90%heavy mineral oil and from about 10% to about 50% paraffin wax (having amelting point of about 51-53° C.) produced good to excellent qualityfoams that had a collapse time of about more than 2 minutes or aboutmore than 3 minutes at 36° C. Excellent foams that were stable for morethan 3 minutes were obtained in formulations having from about 15% toabout 50% paraffin wax 51-53° C. On the other hand formulations withparaffin wax 51-53° C., 5% produced poor foam whilst 7.5% generated onlyfairly good foam.

Also formulations containing about 60% heavy or light mineral oil andabout 40% paraffin wax (having a melting point of about 42-44° C.)produced excellent quality foams that displayed a collapse time of aboutor more than 1 minute or more than 2 minutes at 36° C. depending on thepropellant. On the other hand formulations with 20% of 42-44 resulted ina poor quality.

In an embodiment foam quality may be improved by increasing thepropellant, by say aliqots of 2% or 4%, for example, from 8% to about12%. The actual amount of propellant increase that is suitable should betitrated from formulation to formulation.

Furthermore, formulations containing between about 80% and about 90%heavy mineral oil and between about 10% and about 20% paraffin wax(having a melting point of about 58-62° C.) produced excellent qualityfoams, having low density (between 0.1 and 0.2 g/mL) that exhibited acollapse time of about or more than 3 minutes at 36° C.

Furthermore, different oleaginous foam formulation consisting of 80% ofvarious oils and 20% paraffin wax (51-53° C.), or consisting of 80%heavy mineral oil and 20% paraffin wax (51-53° C.) and variouspropellants or consisting of heavy mineral oil between about 60%-80% andvarious waxes between about 20%-40% produced quality foams that showed acollapse time of about or more than 2 minutes or more than 3 minutes at36° C.

Furthermore, oleaginous foam formulation consisting of 80% heavy mineraloil and 20% paraffin wax (51-53° C.) showed physical stability inaccelerated stability tests. There was hardly any change in foamquality, density or collapse time after 2 months of storage at 40° C. Adecrease in formulation shakability was detected which may be explainedby a partial solidification of the wax content with time. It may beovercome inter alia by increasing the propellant concentration of theformulation to about 12%, or by using a propellant having a higher vaporpressure such as propellant comprising propane.

These results were surprising as no known foam stabilizing agent such assurfactants was present. Moreover, no fatty alcohol or fatty acid wasneeded, and formulations containing only hydrorphobic solvents and waxesgenerated thermally stable quality foams.

It has further been found that for high concentrations of wax, theinclusion of higher amounts of propellant was found useful in order toimprove the flowability of the formulation within the canister, asindicated by the shakability results.

In one or more embodiments there is provided a foamable carriercomposition comprising a solvent, a wax and a liquefied or compressedgas propellant wherein the formulation provides upon dispensing abreakable foam of quality which has a collapse time at 36° C. of aboutor more than 1 minute. In one or more embodiments, the solvent is ahydrophobic solvent. In one or more embodiments, the hydrophobic solventis mineral oil. In one or more embodiments, the wax is a paraffin wax.In one or more embodiments, the wax is a hydrogenated caster oil. In oneor more embodiments, the wax is a beeswax.

In one or more embodiments there is provided a foamable carriercomposition comprising a hydrophobic solvent between about 50% to about90% by weight of formulation, a wax between about 10% to about 50% byweight of formulation and a liquefied or compressed gas propellantwherein the formulation provides upon dispensing a breakable foam ofquality which has a collapse time at 36° C. of about or more than 1minute. In one or more embodiments the composition further comprises oneor more active agents.

In one or more embodiments there is provided a foamable carriercomposition comprising a solvent selected from a list consisting of acapric/caprylic triglycerides, PPG-15 stearyl ether, isopropylpalmitate, isopropyl myristate, octyldodecanol, between about 50% toabout 90% by weight of formulation, wax between about 10% to about 50%by weight of formulation and a liquefied or compressed gas propellantwherein the formulation provides upon dispensing a breakable foam ofquality which has a collapse time at 36° C. of about or more than 1minute. In one or more embodiments the composition further comprises oneor more active agents.

In one or more embodiments there is provided a foamable carriercomposition comprising a hydrophobic solvent between about 50% to about90% by weight of formulation, wax between about 10% to about 50% byweight of formulation and a liquefied or compressed gas propellant wherethe propellant is hydrocarbon or hydrofluorocarbon propellant which mayselected from a the group consisting of propane, butane, isobutene ormixtures of two or three thereof, AP-70, A-46, Dymel 134a or mixtures oftwo or more thereof, wherein the formulation provides upon dispensing abreakable foam of quality with a collapse time at 36° C. of about ormore than 1 minute. In one or more embodiments the composition furthercomprises one or more active agents.

In one or more embodiments inclusion of higher amounts of propellantimproves the flowability of the formulation. In one or more embodimentsthe improvement is more pronounced where there are high amounts of waxeswithin the canister.

Furthermore, the formulations of the present invention comprising ahydrophobic solvent, for example, mineral oil, and a wax, for example, aparaffin wax 51-53° C., and a propellant in an effective amount canprovide foams of good quality in the presence of various activeingredients. In the context herein active pharmaceutical ingredients andactive cosmetic ingredients are collectively termed “active agent” or“active agents”. Formulations, for example, comprising minocycline HCl,mometasone fuorate, calcitriol and lidocaine produced breakable foams ofquality which are stable and have a collapse time at 36° C. of about ormore than 1 minute.

In one or more embodiments there is provided a foamable carriercomposition comprising a solvent, a wax and a liquefied or compressedgas propellant and one or more active ingredients wherein theformulation provides upon dispensing a breakable foam of quality whichhas a collapse time at 36° C. of about more than 1 minute. In one ormore embodiments, the solvent is a hydrophobic solvent. In one or moreembodiments, the hydrophobic solvent is mineral oil. In one or moreembodiments, the wax is a paraffin wax. In one or more embodiments, thewax is a hydrogenated caster oil. In one or more embodiments, the wax isa beeswax.

In one or more embodiments, the active agent is a tetracycline. In oneor more embodiments, the tetracycline active agent is aminocycline HCl.In one or more embodiments, the active agent is a benzoyl peroxide. Inone or more embodiments, the active agent is mometasone fuorate. In oneor more embodiments, the active agent is calcitriol or another vitamin Dderivative. In one or more embodiments, the active agent is lidocaine.

In one or more embodiments, the composition is essentially free ofpolyols.

In one or more embodiments, composition is capable of providingintradermal delivery of the active agent into the skin with minimal ornegligible transdermal delivery.

In one or more embodiments, the composition is for use in eyeinfections.

In one or more embodiments, the composition is physically stable for atleast two months.

In one or more embodiments, there is provided a substantially surfactantand foam adjuvant free composition comprising:

-   -   a) about 50% to about 90% by weight of a hydrophobic solvent;    -   b) an oleaginous foaming agent comprising        -   i) about 10% to about 50% by weight of paraffin wax;    -   c) an active agent,    -   d) a liquefied or compressed gas propellant    -   wherein the percent by weight is based on weight of foamable        composition; wherein the ratio of composition other than        propellant to propellant is from about 100:3 to about 100:30;    -   wherein upon dispensing the foamable carrier composition forms a        breakable foam that is stable, yet breaks easily upon        application of shear force, and    -   wherein the active agent is compatible with in the formulation;        wherein the formulation provides upon dispensing a breakable        foam of quality which has a collapse time at 36° C. of about        more than 1 minute.

It was observed that when a more solid paraffin wax was used thestabilty of the formulation was improved yet shakability decreased(compare samples 023, 024 to samples 031, 032 respectively and alsocompare samples 035 to sample 013 respectively). It was also observedthat the when light mineral oil was used as opposed to heavy mineral oilthe shakability was improved (compare samples 029, 030 to samples 023,024 respectively). It may be, without being bound by any theory, thatapart from any other chemical differences between the different waxes,the observations may be accounted for in part or entirety by the longerwax chain lengths in the higher melting point parafin waxes.

Hydrophobic Solvent

In an embodiment, the composition of the present invention comprises atleast one hydrophobic organic solvent. A “hydrophobic organic solvent”(also termed “hydrophobic solvent”) as used herein refers to a materialhaving solubility in distilled water at ambient temperature of less thanabout 1 gm per 100 mL, more preferably less than about 0.5 gm per 100mL, and most preferably less than about 0.1 gm per 100 mL. It is liquidat ambient temperature. The identification of a “hydrophobic solvent”,as used herein, is not intended to characterize the solubilizationcapabilities of the solvent for any specific active agent or any othercomponent of the foamable composition. Rather, such term is provided toaid in the identification of materials suitable for use as a hydrophobicsolvent in the foamable compositions described herein.

In one or more embodiments the hydrophobic solvent is present at aconcentration of about 40% to about 90%; or about 50% to about 95%; orabout 60% to about 95% or about 65% to about 90%; or about 70% to about90% or about 75% to about 85%.

In one or more embodiments, the composition of the present inventioncomprises at least one hydrophobic solvent, selected from the groupconsisting of a mineral oil, a hydrocarbon oil, an ester oil, a liquidtriglyceride oil, an oil of plant origin, an oil from animal origin, anunsaturated or polyunsaturated oil, a diglyceride, a PPG alkyl ether anda silicone oil.

As exemplified herein, members of each of the above listed groups ofhydrophobic solvents have been found to be compatible with hydrophobictetracyclines, such as minocycline and doxycycline.

Non-limiting examples of hydrocarbon oils include mineral oil, liquidparaffin, an isoparaffin, a polyalphaolefin, a polyolefin,polyisobutylene, a synthetic isoalkane, isohexadecane and isododecane.

Non-limiting examples of ester oils include alkyl benzoate, alkyloctanoate, C12-C15 alkyl benzoate, C12-C15 alkyl octanoate, arachidylbehenate, arachidyl propionate, benzyl laurate, benzyl myristate, benzylpalmitate, bis(octyldodecyl stearoyl) dimer dilinoleate, butylmyristate, butyl stearate, cetearyl ethylhexanoate, cetearylisononanoate, cetyl acetate, cetyl ethylhexanoate, cetyl lactate, cetylmyristate, cetyl octanoate, cetyl palmitate, cetyl ricinoleate, decyloleate, diethyleneglycol diethylhexanoate, diethyleneglycol dioctanoate,diethyleneglycol diisononanoate, diethyleneglycol diisononanoate,diethylhexanoate, diethylhexyl adipate, diethylhexyl malate,diethylhexyl succinate, diisopropyl adipate, diisopropyl dimerate,diisopropyl sebacate, diisosteary dimer dilinoleate, diisostearylfumerate, dioctyl malate, dioctyl sebacate, dodecyl oleate, ethylhexylpalmitate, ester derivatives of lanolic acid, ethylhexyl cocoate,ethylhexyl ethylhexanoate, ethylhexyl hydroxystarate, ethylhexylisononanoate, ethylhexyl palmytate, ethylhexyl pelargonate, ethylhexylstearate, hexadecyl stearate, hexyl laurate, isoamyl laurate, isocetylisocetyl behenate, isocetyl lanolate, isocetyl palmitate, isocetylstearate, isocetyl salicylate, isocetyl stearate, isocetyl stearoylstearate, isocetearyl octanoate, isodecyl ethylhexanoate, isodecylisononanoate, isodecyl oleate, isononyl isononanoate, isodecyl oleate,isohexyl decanoate, isononyl octanoate, isopropyl isostearate, isopropyllanolate, isopropyl laurate, isopropyl myristate, isopropyl palmitate,isopropyl stearate, isostearyl behenate, isosteary citrate, isostearylerucate, isostearyl glycolate, isostearyl isononanoate, isostearylisostearate, isostearyl lactate, isostearyl linoleate, isostearyllinolenate, isostearyl malate, isostearyl neopentanoate, isostearylpalmitate, isosteary salicylate, isosteary tartarate, isotridecylisononanoate, isotridecyl isononanoate, lauryl lactate, myristyllactate, myristyl myristate, myristyl neopentanoate, myristylpropionate, octyldodecyl myristate, neopentylglycol dicaprate, octyldodecanol, octyl stearate, octyl palmitate, octyldodecyl behenate,octyldodecyl hydroxystearate, octyldodecyl myristate, octyldodecylstearoyl stearate, oleyl erucate, oleyl lactate, oleyl oleate, propylmyristate, propylene glycol myristyl ether acetate, propylene glycoldicaprate, propylene glycol dicaprylate, propylene glycol dicaprylate,maleated soybean oil, stearyl caprate, stearyl heptanoate, stearylpropionate, tocopheryl acetate, tocopheryl linoleate, glyceryl oleate,tridecyl ethylhexanoate, tridecyl isononanoate and triisocetyl citrate.

Non-limiting examples of liquid triglycerides and oils of plant origininclude alexandria laurel tree oil, avocado oil, apricot stone oil,barley oil, borage seed oil, calendula oil, canelle nut tree oil, canolaoil, caprylic/capric triglyceride castor oil, coconut oil, corn oil,cotton oil, cottonseed oil, evening primrose oil, flaxseed oil,groundnut oil, hazelnut oil, glycereth triacetate, glyceroltriheptanoate, glyceryl trioctanoate, glyceryl triundecanoate, hempseedoil, jojoba oil, lucerne oil, maize germ oil, marrow oil, millet oil,neopentylglycol dicaprylate/dicaprate, olive oil, palm oil,passionflower oil, pentaerythrityl tetrastearate, poppy oil, propyleneglycol ricinoleate, rapeseed oil, rye oil, safflower oil, sesame oil,shea butter, soya oil, soybean oil, sweet almond oil, sunflower oil,sysymbrium oil, syzigium aromaticum oil, tea tree oil, walnut oil, wheatgerm glycerides and wheat germ oil.

Non-limiting examples of PPG alkyl ethers include PPG-2 butyl ether,PPG-4 butyl ether, PPG-5 butyl ether, PPG-9 butyl ether, PPG-12 butylether, PPG-14 butyl ether, PPG-15 butyl ether, PPG-15 stearyl ether,PPG-16 butyl ether, PPG-17 butyl ether, PPG-18 butyl ether, PPG-20 butylether, PPG-22 butyl ether, PPG-24 butyl ether, PPG-26 butyl ether,PPG-30 butyl ether, PPG-33 butyl ether, PPG-40 butyl ether, PPG-52 butylether, PPG-53 butyl ether, PPG-10 cetyl ether, PPG-28 cetyl ether,PPG-30 cetyl ether, PPG-50 cetyl ether, PPG-30 isocetyl ether, PPG-4lauryl ether, PPG-7 lauryl ether, PPG-2 methyl ether, PPG-3 methylether, PPG-3 myristyl ether, PPG-4 myristyl ether, PPG-10 oleyl ether,PPG-20 oleyl ether, PPG-23 oleyl ether, PPG-30 oleyl ether, PPG-37 oleylether, PPG-40 butyl ether, PPG-50 oleyl ether and PPG-11 stearyl ether.Preferred PPG alky ethers according to the present invention includePPG-15 stearyl ether, PPG-2 butyl ether and PPG-9-13 butyl ether.

Non-limiting examples of oils from animal origin include herring oil,cod-liver oil and salmon oil.

The hydrophobic solvent may be an emollient, i.e., a hydrophobic liquidhaving a softening or soothing effect especially to the skin. In someembodiments the liquid oil may contain a solid or semi solid hydrophobicmatter at room temperature.

Essential oil, which is usually a concentrated, hydrophobic liquidcontaining volatile aroma compounds from plants usually conveyingcharacteristic fragrances. Non limiting examples include lavender,peppermint, and eucalyptus. A therapeutic oil is a hydrophobic liquidwhich is said to have a therapeutic effect or to have associated with itcertain healing properties. Therapeutic oils contain active biologicallyoccurring molecules and, upon topical application, exert a therapeuticeffect. Non limiting examples include manuka oil, rosehip oil, whichcontains retinoids and is known to reduce acne and post-acne scars, andtea tree oil, which possesses antimicrobial activity includingantibacterial, antifungal and antiviral properties as well as any othertherapeutically beneficial oil known in the art of herbal medication.Many essential oils are considered “therapeutic oils.” Other nonlimiting examples of essential oils are basil, camphor, cardamom,carrot, citronella, clary sage, clove, cypress, frankincense, ginger,grapefruit, hyssop, jasmine, lavender, lemon, mandarin, marjoram, myrrh,neroli, nutmeg, petitgrain, sage, tangerine, vanilla and verbena.

Some embodiments include silicone oils. Non-limiting examples ofsilicone oils include a cyclomethicone, dimethicone, a polyalkylsiloxane, a polyaryl siloxane, a polyalkylaryl siloxane, a polyethersiloxane copolymer, a poly(dimethylsiloxane)-(diphenyl-siloxane)copolymer, a dimethyl polysiloxane, an epoxy-modified silicone oil, afatty acid-modified silicone oil, a fluoro group-modified silicone oil,a methylphenylpolysiloxane, phenyl trimethicone and a polyethergroup-modified silicone oil. In some embodiments, the silicone oil iscyclomethicone, cyclotetrasiloxane, cyclohexasiloxane,phyenyltrimethicone, Dow corning 246 Fluid (d6+d5) (cyclohexasiloxane &cyclopentasiloxane), Dow Corning 244 Fluid (cyclotetrasiloxane),Cyclomethicone 5-NF (cyclopentasiloxane), stearyl dimethicone,phenyltrimethicone, cetyl dimethicone, caprylyl methicone, PEG/PPG 18/18dimethicone, or dimethiconol.

In one or more embodiments, the hydrophobic solvent may be selected fromcapric/caprylic triglycerides, cyclomethicone; isopropyl myristate,isopropyl palmitate, PPG-15 stearyl ether; octyldodecanol;isohexadecanol, diisopropyl adipate; cetearyl octanoate; MCT oil; heavymineral oil; light mineral oil; coconut oil and soybean oil.

Mixtures of two or more hydrophobic solvents in the same foamablecomposition is contemplated. Furthermore, in certain embodiments, theuse of mixtures of two or more hydrophobic solvents is preferred.

Yet, in certain embodiments, the hydrophobic solvent is a mixture of oneor more liquid hydrophobic solvents, as listed above, together with anadditional hydrophobic substance, which is not liquid (such aspetrolatum), provided that the resultant mixture of all hydrophobicsubstances, is liquid at ambient temperature. In an embodiment theresultant mixture upon including propellant is liquid at ambienttemperature. In certain embodiments the main hydrophobic substance inthe formulation is a petrolatum, which is a semi solid, in combinationwith at least one liquid hydrophobic solvent. For example petrolatum maybe added to provide a degree of occlusivity so that the formulation whenapplied to a skin surface can operate to increase skin moisture and orreduced transdermal water loss. In certain other embodiments a liquidhydrophobic solvent is not added. Fluidity of the composition can beachieved by utilizing liquidizing solvents (e.g. C12 C15 Alkyl benzoate)and or liquefied propellants and or optionally liquid adjuvants.Inclusion of higher amounts of propellant was found useful in order toimprove flowability of the formulation from the canister or by usingpropellants having a higher vapor pressure.

Fatty Alcohol

If at all present, the fatty alcohol is selected from the groupconsisting of fatty alcohols having 15 or more carbons in their carbonchain, such as cetyl alcohol and stearyl alcohol (or mixtures thereof).Other examples of fatty alcohols are arachidyl alcohol (C20), behenylalcohol (C22), tetracosanol, hexacosanol, octacosanol, triacontanol,tetratriacontanol, 1-triacontanol (C30), as well as alcohols with longercarbon chains (up to C50). In one or more other embodiments, the fattyalcohol is selected from the group consisting of fatty alcohols having14 or less carbons in their carbon chain, such as lauryl alcohol andmyristyl alcohol. In an embodiment the fatty alcohol is a solid at roomtemperature.

Fatty Acid

If at all present the fatty acid can have 16 or more carbons in itscarbon chain, such as hexadecanoic acid (C16), heptadecanoic acid,stearic acid (C18), arachidic acid (C20), behenic acid (C22),tetracosanoic acid (C24), hexacosanoic acid (C26, heptacosanoic acid(C27), octacosanoic acid (C28), triacontanoic acid, dotriacontanoicacid, tritriacontanoic acid, tetratriacontanoic acid andpentatriacontanoic acid. as well as fatty acids with longer carbonchains (up to C50), or mixtures thereof. In one or more otherembodiments, the fatty acid is selected from the group consisting offatty alcohols having 14 or less carbons in their carbon chain, such asdodecanoic acid, myristic acid, myristoleic acid, and lauric acid. In anembodiment the fatty acid is a solid at room temperature.

Waxes

The foaming agent includes a wax. The wax which usually acts as a typeof foam adjuvant is included in the foamable compositions to evolve thefoaming property of the composition and/or to stabilize the foam. Waxrefers to paraffin wax or beeswax or hydrogenated castor oil or anothersubstance with similar properties. The term wax refers to a class ofsubstances with properties similar to beeswax, in respect of (i) plasticbehavior at normal ambient temperatures, a melting point aboveapproximately 45° C., (ii) a relatively low viscosity when melted(unlike many plastics); and (iii) hydrophobic nature. Suitable exemplarywaxes which can be incorporated into the formulation include animal,vegetable, mineral or silicone based waxes which may be natural orsynthetic such as, for example: beeswax, Chinese wax, lanolin (woolwax), shellac wax, bayberry wax, candelilla wax, carnauba wax, castorwax, esparto wax, japan wax, ouricury wax, rice bran wax, soy wax,hydrogenated oil such ashydrogenated castor oil, hydrogenated cottonseedoil, or hydrogenated jojoba oil, mink wax, motan wax, ouricury wax,ozokerite, PEG-6 beeswax, rezowax, spent grain wax, stearyl dimethicone,paraffin waxes, such as paraffin 42-44, 51-53 58-62 wax, and the likeand mixtures thereof. In one or more embodiments the wax is selectedfrom a list comprising of a solid wax, an animal wax, a vegetable wax, amineral wax, a natural wax or a synthetic wax. In certain embodimentsthe term wax can extend to hydrogenated oils. In one or more preferredembodiments, the wax is a beeswax or hydrogenated castor oil.

In one or more embodiments the range of ratio of wax/hydrophobic solventcan be about 100:1 to about 1:100; or about 90:1 to about 1:45; or about80:1 to about 1:40; or about 70:1 to about 1:35; or about 60:1 to about1:30; or about 50:1 to about 1:25; or about 40:1 to about 1:20; or about30:1 to about 1:15; or about 20:1 to about 1:10; or about 15:1 to about1:5; or about 10:1 to about 1:1; or any ranges in between such as 1:20to 20:1, or preferably from 1:15 to 15:1. Preferably the range of theratio of wax/hydrophobic solvent can be selected from a list comprisingof: about 1:10; about 10:1; about 1:9 to about 9:1; or about 1:7 toabout 7:1; or about 3:17 to about 17:3; or about 1:4 to about 4:1; orabout 1:3 to about 3:1; or about 2:5 to about 5:2; or about 3:7 to about7:3; or about 1:2 to about 2:1; or about 5:9 to about 9:5; or about 2:3to about 3:2; or about 9:11 to about 11:9;

In one or more embodiments Shea butter may be further added to thecomposition. Shea butter may, for example, be used in addition toparaffin wax or bees wax or hydrogenated caster oil in order to enhancefoam quality or to complement the action of one or more of them.

In one or more embodiments the foaming agent can further include be afatty alcohol and shea butter, or a fatty acid and shea butter or acombination of a fatty alcohol and a fatty acid and shea butter.

Propellant

The composition requires the addition of a propellant in order togenerate a foam.

Suitable propellants include volatile hydrocarbons such as butane,propane, isobutene or mixtures thereof. In one or more embodiments ahydrocarbon mixture AP-70 is used. In one or more other embodiments alower pressure hydrocarbon mixture AP-46 is used. Both contain butane,propane, isobutene although in different proportions. AP-70 is composedof about 50% w/w of propane, about 20% w/w of isobutane and about 30%w/w of propane. AP-46 is composed of about 16% w/w of propane, about 82%w/w of isobutane and about 2% w/w of propane. Hydro fluorocarbon (HFC)propellants are also suitable as propellants in the context disclosedherein. Exemplary HFC propellants include 1,1,1,2 tetrafluorethane(Dymel 134), and 1,1,1,2,3,3,3 heptafluoropropane (Dymel 227). Dimethylether is also useful. In one or more embodiments use of compressed gases(e.g., air, carbon dioxide, nitrous oxide, and nitrogen) is alsopossible.

In one or more embodiments a combination of at least two propellants,selected from HFC, hydrocarbon propellants, dimethyl ether andcompressed gases is contemplated.

Yet, in additional embodiments, the propellant is a self-foamingpropellant, i.e., a volatile liquid having a boiling point of less thanthe temperature of the target treatment site (such as the skin). Anexample of a post-foaming propellant is isopentane (bp=26° C.)

Any concentration of the propellant, which affords an acceptable foam,is useful in accordance with the present invention. In certainembodiments the propellant makes up between about 1% and about 30% ofthe foamable composition, or about 3% and 25%; and in certain preferredembodiments between about 5% and about 16% of the composition. Inpreparing the formulations the ingredients other than propellant arecombined to 100% and the propellant is added thereafter so that theratio of formulation to propellant can range from 100:1 to 100:30; 100:4to 100:25 or preferably 100:5 to 100:16. Yet, in additional embodiments,the ratio of composition other than propellant to propellant is betweenabout 100:20 and about 100:50.

Due to environmental concerns, as well as compatibility considerations,propellants that are not environmentally friendly are in one or moreembodiments to be avoided. So chlorofluoro carbons (CFC's), which areknown to damage the ozone layer in the atmosphere, are essentiallyexcluded from the formulations.

In one or more embodiments, the propellant can also be used to expelformulation using a bag in can system or a can in can system as will beappreciated by someone skilled in the art. In certain embodiments thepart of the propellant system is in the formulation and part separatefrom the formulation. In this way it is possible to reduce the amount ofsurfactant in the formulation but still provide good expulsion from thecanister, where the foamable formulation is expelled quickly but withoutjetting or noise.

In one or more embodiments a foam formulation is expelled from astandard pressurized canister where the propellant is part offormulation. Formulations can be expelled or helped to be expelled byusing propellant which is separate from the formulation using a bag incan or can in can system. Although, these systems can be used withcompressed air the pressure may not be sufficient to expel theformulation through the device and higher pressure propellant such asAP70 should be selected. In one or more embodiments, the formulation ispackaged in bag in can systems or in can in can system. In one or moreembodiments, the formulation is expelled from the canister using thepressure provided by the propellant mixed with the formulation. In oneor more embodiments, the formulation is expelled from the canister usingthe pressure provided by the propellant stored in a compartmentsurrounding the formulation. According to other embodiments part of thepropellant system is in the formulation and part of the propellantsystem is separate from the formulation, which is used to expel saidformulation using a bag or can in can system. In this way it is possibleto reduce the amount of propellant within the formulation and avoidunwanted gaseous effects, for example in vaginal applications, but stillprovide good expulsion from the canister, where the foamable formulationis expelled sufficiently quickly but without jetting or noise. So by wayof example, between about 1% to 3%; or between about 2% to 4%; betweenabout 3% to 5% propellant (ratio of formulation to propellant of 100:1to 3; 100:2 to 4; 100:3 to 5; respectively) is part of the formulationand a further amount of propellant is separate form the formulation andhelps expel the formulation. In one or more embodiments a similar amountof propellant is in the formulation and a pump or other mechanical meansis used to provide the additional expulsion force.

Modulating Agent

In one or more embodiments the modulating agent is used in a waterlesscomposition which is surfactant and adjuvant free. The term modulatingagent is used to describe an agent which can improve the stability of orstabilize a carrier or a foamable composition and/or an active agent bymodulating the effect of a substance or residue present in the carrieror composition. The substance or residue may, for example, be acidic orbasic or buffer system (or combinations thereof) and potentially alteran artificial pH in a waterless or substantially non-aqueousenvironment, such as, by acting to modulate the ionic or polarcharacteristics and any acidity or basesity balance of a waterless orsubstantially non-aqueous carrier, composition, foamable carrier orfoamable composition or resultant foam or it may be a chelating orsequestering or complexing agent or it may be one or more metal ionswhich may act as a potential catalyst in a waterless or substantiallynon-aqueous environment or it may be an ionization agent or it may be anoxidizing agent.

In an embodiment, the modulating or additional component is a pHadjusting agent or a buffering agent and can be any of the knownbuffering systems used in pharmaceutical or cosmetic formulations aswould be appreciated by a man of the art. It can also be an organicacid, a carboxylic acid, a fatty acid an amino acid, an aromatic acid,an alpha or beta hydroxyl acid an organic base or a nitrogen containingcompound.

In one or more further embodiments the modulating agent is used todescribe an agent, which is a chelating or sequestering or complexingagent that is sufficiently soluble or functional in the waterlesssolvent to enable it to “mop up” or “lock” metal ions such as EDTA orother such pharmaceutically or cosmetically acceptable.

Modulating agents may be added to the compositions of the subjectinvention, preferably from about 0.1% to about 10%, more preferably fromabout 1% to about 5%, of the composition. Where the active agent itselfis the modulating agent alone or in combination with another modulatingagent it will be added at an effective dose which may be outside theseranges. For example azaleic acid may be at about 15% of the composition.In an embodiment sufficient modulating agent is added to achieve anartificial pH in which the active agent is preferably stable. Suchartificial pH may be acidic, maybe basic or may be neutral

Further detail regarding modulating agents is found in co-pendingPublished U.S. Patent Application 2008/0206159, which is herebyincorporated in its entirety by reference.

The modulating agent to the foamable composition is useful forstabilizing pharmaceutical and cosmetic active agents which are unstablein certain pH conditions. It is known, for example, that active agents,which contain ester bond in their structure, tend to undergo hydrolysisof the ester bond at basic pH levels. Therefore, the addition of anagent, avoids the formation of basic pH condition, and thus, preventsdegradation of such active agents. Many steroid compounds are known toundergo rearrangement at high pH, and again, adding an acidic modulatingagent helps prevent such degradation. Another example of a pH-sensitiveactive agent is vitamin D, which degrades at low pH levels. In such acase, the addition of a basic modulating agent, such as triethanolamineis useful to maintain acceptable stability of this active agent.

It is important to maintain skin surface pH in order to preventsusceptibility to bacterial skin infections or skin damage and disease.Thus, adding a modulating agent, which contributes to the stabilizationof skin pH at the desirable level, is advantageous.

In the same fashion, adding an acidic modulating agent to a foamablecomposition, which is intended for vaginal application is advantageous,since better protection against vaginal infection is attained in pHlower than 4.

In one or more embodiments, the modulating agent may also be apreservative or an antioxidant or an ionization agent. Any preservative,antioxidant or ionization agents suitable for pharmaceutical or cosmeticapplication may be used. Non-limiting examples of antioxidants aretocopherol, tocopherol succinate, ascorbic acid (vitamin C) and itssalts, propyl galate, butylated hydroxy toluene and butyl hydroxyanisol. Non-limiting examples of positive ionization agents are benzylconium chloride, and cetyl pyridium chloride. Non-limiting examples ofnegative ionization agents are sodium lauryl sulphate, sodium lauryllactylate and phospholipids. In one or more embodiments the modulatingagent is a flavonoid for example quercitin and/or rutin.

A safe and effective amount of an anti-oxidant/radical scavenger may beadded to the compositions of the subject invention, preferably fromabout 0.1% to about 10%, more preferably from about 1% to about 5%, ofthe composition.

In one or more embodiments the modulating agent used is compatible withthe active ingredient(s).

Ophthalmic Excipients

In one or more embodiments the formulation may comprise excipients thatare suitable for ophthalmic use. By virtue of their suitability forophthalmic use they may in certain embodiments be applicable on othersensitive targets such as for use internal and or external wounds orburns or in body cavities. Excipients selected as part of a drug carrierthat can be used with the active pharmaceutical ingredients areidentified by compatibility studies with active ingredients to ascertainwhich are compatible for use with the active pharmaceutical ingredients,for example, by examining which do not react with and or promote breakdown of the active pharmaceutical ingredients.

Not all excipients are appropriate for opthlmic use. Some may not beapproved and require additional studies to achieve regulatory approval.Some may be eliminated as incompatible with the active ingredient andsome may be eliminated agents because of physical considerations (e.g.as indicated below). Some may have or require that an effect be modifiedby the addition of other ingredients (e.g. such as rheology modifiers).

Oleaginous ointments are viscous preparations, which remain viscous whenapplied to the skin or other body surfaces; and they require extensiverubbing. Because of their viscosity, eye ointments cause blurred visionand consequent low tolerability, especially for long term treatment.Because of their high viscosity, drugs are trapped in the vehicle andcannot migrate through to their target site of action, for example, theskin or the eye.

Liquid, non viscous oleaginous medications are also disadvantageous, asthey spill easily and thus, are very inconvenient to use. In eyetreatment, liquid drops are difficult to apply and they require lying onthe back at rest for accurate administration. Furthermore, because oftheir low viscosity, liquid oil vehicles cannot carry suspended drugs,which tend to precipitate and if the viscosity is not high enough,thereby impairing the uniformity of the therapeutic product.

In one or more embodiments the formulations are not highly viscous. Inone or more other embodiments the formulations do not provide lowviscosity. In one or more embodiments the formulations are thixotropicso that on application of shear force their viscosity decreases and theybecome more flowable. On one or more embodiments the formulations arefoams which are breakable on shear force. In one or more embodiments thefoams are based on thixotropic gel formulations. In one or moreembodiments the viscosity of the formulation prior to addition ofpropellant is more than about 1000 cps and less than about 25,000 cps.

Additional Components

In an embodiment, a composition disclosed herein includes one or moreadditional components. Such additional components include but are notlimited to anti perspirants, anti-static agents, bulking agents,cleansers, colorants, skin conditioners, deodorants, diluents, dyes,fragrances, hair conditioners, herbal extracts, humectants, keratolyticagents, modulating agents, pearlescent aids, perfuming agents, pHmodifying or stabilizing agents, skin penetration or permeationenhancers, softeners, solubilizers, sunscreens, sun blocking agents,sunless tanning agents, viscosity modifiers, flavanoids and vitamins. Asis known to one skilled in the art, in some instances a specificadditional component may have more than one activity, function oreffect.

In certain embodiments, the additional component is an oil solublepreservative, or an oil soluble antioxidant, or an oil soluble radicalscavenger, or an oil soluble complexing agent, or an oil soluble pigmentor dye.

Definitions

All % values are provided on a weight (w/w) basis.

By the term “about” herein it is meant that a figure or range of figurescan vary plus or minus up to 30%. So in this embodiment if a figure of“about 1” is provided then the amount can be up to 1.3 or from 0.70. Inother embodiments it can reflect a variation of plus or minus 20%. Instill further embodiments it can describe a variation of plus or minus10%. In still further embodiments it can describe a variation of plus orminus 5%. As will be appreciated by one of the art there is somereasonable flexibility in formulating compositions such that where oneor more ingredients are varied successful formulations may still be madeeven if an amount falls slightly outside the range. Therefore, to allowfor this possibility amounts are qualified by about. In one or moreother embodiments the figures may be read without the prefix about.

The term “waterless,” as used herein, means that the compositioncontains no, or substantially no, free or unassociated or absorbedwater. Similarly, “waterless” or “substantially waterless” carrierscontain at most incidental and trace amounts of water.

By the term “single phase” herein it is meant that after addition ofpropellant to the composition or carrier, the liquid components of thefoamable composition or carrier are fully miscible, and the solidcomponents if any, are either dissolved or suspended in the composition.By substantially a single phase is meant that the composition or carrierafter addition of propellant is primarily or essentially a single phaseas explained above, but may also have present a small amount of materialwhich is capable of forming or may form a separate phase amounting toless than about 5% of the composition or carrier after the addition ofpropellant, preferably less than about 3%, and more preferably less thanabout 1%.

The term “unstable active agent” as used herein, means an active agentwhich is oxidized and/or degraded within less than a day, and in somecases, in less than an hour upon exposure to air, light, skin or waterunder ambient conditions.

The term “co-surfactant” as used herein, means a molecule which on itsown is not able to form and stabilize satisfactorily an oil in wateremulsion but when used in combination with a surfactant theco-surfactant has properties, which can allow it to help surfactants tocreate an emulsion and can boost the stabilizing power or effect of thesurfactant and can include, for example, a fatty alcohol, such as cetylalcohol or a fatty acid such as stearic acid. Cetyl alcohol is a waxyhydrophobic substance that can be emulsified with water using asurfactant. Some substances may have more than one function and forexample, fatty alcohols can in some formulations act as a co-solvent. Incertain circumstances a co-surfactant can itself be converted in to asurfactant or soap by, for example, adding a base, such as,triethanolamine to a fatty acid like stearic acid.

The identification of a “polyol”, as used herein, is an organicsubstance that contains at least two hydroxy groups in its molecularstructure.

In one or more embodiments, the polyol is a diol (a compound thatcontains two hydroxy groups in its molecular structure). Examples ofdiols include propylene glycol (e.g., 1,2-propylene glycol and1,3-propylene glycol), butanediol (e.g., 1,2-butanediol, 1,3-butanediol,2,3-butanediol and 1,4-butanediol), butanediol (e.g., 1,3-butanediol and1,4-butenediol), butynediol, pentanediol (e.g., pentane-1,2-diol,pentane-1,3-diol, pentane-1,4-diol, pentane-1,5-diol, pentane-2,3-dioland pentane-2,4-diol), hexanediol (e.g., hexane-1,6-diol hexane-2,3-dioland hexane-2,56-diol), octanediol (e.g., 1,8-octanediol), neopentylglycol, 2-methyl-1,3-propanediol, diethylene glycol, triethylene glycol,tetraethylene glycol, dipropylene glycol and dibutylene glycol.

In one or more embodiments, the polyol is a triol (a compound thatcontains three hydroxy groups in its molecular structure), such asglycerin, butane-1,2,3-triol, butane-1,2,4-triol and hexane-1,2,6-triol.

In one or more embodiments, the polyol is a saccharide. Exemplarysaccharides include, but are not limited to monosaccharide,disaccharides, oligosaccharides and sugar alcohols.

A monosaccharide is a simple sugar that cannot be hydrolysed to smallerunits. Empirical formula is (CH2O)n and range in size from trioses (n=3)to heptoses (n=7). Exemplary monosaccharide compounds are ribose,glucose, fructose and galactose.

Disaccharides are made up of two monosaccharides joined together, suchas sucrose, maltose and lactose.

In one or more embodiments, the polyol is a sugar alcohol (also known asa polyol, polyhydric alcohol, or polyalcohol) is a hydrogenated form ofsaccharide, whose carbonyl group (aldehyde or ketone, reducing sugar)has been reduced to a primary or secondary hydroxyl group. They arecommonly used for replacing sucrose in foodstuffs, often in combinationwith high intensity artificial sweeteners to counter the low sweetness.Some exemplary sugar alcohols, which are suitable for use according tothe present invention are mannitol, sorbitol, xylitol, maltitol,lactitol. (Maltitol and lactitol are not completely hydrogenatedcompounds—they are a monosaccharide combined with a polyhydric alcohol.)Mixtures of polyols, including (1) at least one polyol selected from adiol and a triol; and (2) a saccharide are contemplated within the scopeof the present disclosure.

According to some embodiments, the composition is polyol-free i.e., freeof polyols. In other embodiments, the composition is substantially freeand comprises less than about 5% final concentration of polyols,preferably less than 2%, more preferably less than 1%. Where aformulation includes insignificant amounts of polyols it is consideredto be essentially free of them.

In an embodiment, the polyol is linked to a hydrophobic moiety. In thecontext of the present disclosure, a polyol linked to a hydrophobicmoiety is still defined as a “polyol” as long as it still contains twoor more free hydroxyl groups.

In an embodiment, the polyol is linked to a hydrophilic moiety. In thecontext of the present disclosure, a polyol linked to a hydrophilicmoiety is still defined “polyol” as long as it still contains two ormore free hydroxyl groups.

The term “water activity” as used herein, activity represents thehydroscopic nature of a substance; or the tendency of a substance thatabsorbs water from its surroundings. Microorganisms require water togrow and reproduce, and such water requirements are best defined interms of water activity of the substrate. The water activity of asolution is expressed as Aw=P/Po, where P is the water vapor pressure ofthe solution and Po is the vapor pressure of pure water at the sametemperature. Every microorganism has a limiting Aw, below which it willnot grow; e.g., for Streptococci, Klebsiella spp, Escherichia coli,Clostridium perfringens, and Pseudomonas spp, the Aw value is 0.95.Staphylococcus aureus is most resistant and can proliferate with an Awas low as 0.86, and fungi can survive at Aw of at least 0.7. In one ormore embodiments, the concentration of the hydrophobic solvent, and/orfoaming agent in the composition is selected to provide an Aw valueselected from the ranges of (1) about 0.8 and about 0.9; (2) about 0.7and about 0.8; and (3) less than about 0.7. Delivering the formulationin a pressurized package does not allow for humidity to be absorbed bythe preparation, and therefore, the water free character of thecomposition cannot be damaged.

In an embodiment no preservative is added because the formulation is awaterless hydrophobic solvent or oil-based formulation having an Aw(Water Activity) value of less than 0.9, less, or less than about 0.8,or less than about 0.7 or less than about 0.6 and preferably less thanabout 0.5 which is below the level of microbial proliferation.

In one or more embodiments, the hydrophobic carrier composition furthercontains an anti-infective agent, selected from the group of anantibiotic agent, an antibacterial agent, an antifungal agent, an agentthat controls yeast, an antiviral agent and an antiparasitic agent. In apreferred embodiment the anti infective agent comprises a tricyclicantibiotic. Not only can combining the anti-infective effect of ahydrophobic carrier composition, with an anti-infective agent can resultin a synergistic effect and consequently higher success rate of thetreatment but the combination with the foaming agent achieves aformulation which is physically stable as demonstrated herein in theExamples. Moreover the use of hydrophobic based water free formulationcan maximize the antimicrobial potential of the formulations. Storage insealed, light and airtight canisters can assist in preserving theformulations.

The identification of a “solvent,” as used herein, is not intended tocharacterize the solubilization capabilities of the solvent for anyspecific active agent or any other component of the foamablecomposition. Rather, such information is provided to aid in theidentification of materials suitable for use as a part in the foamablecarriers described herein.

Substantially Alcohol Free

Lower or short chain alcohols, having up to 5 carbon atoms in theircarbon chain skeleton, such as ethanol, propanol, isopropanol, butanol,iso-butanol, t-butanol and pentanol are considered less desirablesolvents or co-solvents due to their skin-irritating effect. Thus,according to some embodiments, the composition is substantiallyalcohol-free i.e., free of short chain alcohols. In other embodiments,the composition comprises less than about 5% final concentration oflower alcohols, preferably less than 2%, more preferably less than 1%.Where a formulation contains insignificant amounts of short chainalcohols it is considered to be essentially free of them.

Substantially Surfactant Free

Surfactants have been categorized in to various sub classes depending ontheir ionic characteristics, namely non-ionic surfactants, anionic,cationic, zwitterionic, amphoteric and amphiphilic surfactants. The termsurfactant has been often loosely used in the art to include substanceswhich do not function effectively as stand alone surfactants to reducesurface tension between two substances or phases. Reduction of surfacetension can be significant in foam technology in relation to the abilityto create small stable bubbles. For example fatty alcohols, fatty acidsand certain waxes are amphiphatic, are essentially hydrophobic with aminor hydrophilic region and for the purposes of forming an emulsionthey are usually regarded as an oil and thus have a “required” HLBvalue” for the purpose of determining what standard surfactant might beappropriate to use with the oil phase. However unlike standard orcustomary surfactants, these substances are not effective as stand-alonesurfactants in foamable emulsion compositions, because of their veryweak emulsifying capacity and further due to their weak foaming capacityon their own. They are occasionally used in a supporting role asco-emulsifiers, i.e., in combination with a standard surfactant but arecommonly used as thickeners and have successfully been used as foamadjuvants to assist customary surfactants to boost foam quality andstability. For clarification, in the context herein, the term “standardsurfactant” or “customary surfactant” refers herein to customarynon-ionic, anionic, cationic, zwitterionic, amphoteric and amphiphilicsurfactants. A fatty alcohol or a fatty acid and certain waxes are notregarded as a standard surfactant. However, in contrast, an ether or anester formed from such fatty alcohols or fatty acids can be regarded asa customary surfactant.

Generally, surfactants are known to possess irritation potential. Oneway that is used to try and reduce potential irritation and drying ofthe skin or mucosa due to surfactants and their repeated use especiallywhen formulations are to be left on the skin or mucosa rather than beingwashed off is to use essentially or primarily non ionic surfactants atpreferably low concentrations below 5%. The current breakthrough ofidentifying formulations which produce quality breakable foam yetomitting customary surfactants from a composition may contribute toimproved tolerability of such a composition and can be an importantadvantage. This is especially so when a formulation is to be applied toa very sensitive target site, and particularly so on a repeated basis.

Non-limiting examples of classes of customary non-ionic surfactantsinclude: (i) polyoxyethylene sorbitan esters (polysorbates), such aspolysorbate 20, polysorbate 40, polysorbate 60 and polysorbate 80; (ii)sorbitan esters, such as sorbitan monostearate sorbitan monolaurate andsorbitan monooleate; (iii) polyoxyethylene fatty acid esters, such asPEG-8 stearate, PEG-20 stearate, PEG-40 stearate, PEG-100 stearate,PEG-8 laurate, PEG-10 laurate, PEG-12 laurate, PEG-20 laurate, PEG-8oleate, PEG-9 oleate, PEG-10 oleate, PEG-12 oleate, PEG-15 oleate andPEG-20 oleate; (iv) PEG-fatty acid diesters, such as PEG-150 distearate,(v) polyethylene glycol (PEG) ethers of fatty alcohols, such as; (vi)glycerol esters, such as glyceryl monostearate, glyceryl monolaurate,glyceryl monopalmitate and glyceryl monooleate; (vii) PEG-fatty acidmono- and di-ester mixtures; (viii) polyethylene glycol glycerol fattyacid esters; (ix) propylene glycol fatty acid esters; (x) mono- anddiglycerides; (xi) sugar esters (mono-, di- and tri-esters of sucrosewith fatty acids) and (xii) polyethylene glycol alkyl phenols.

In certain embodiments, the composition is free of customarysurfactants, or “surfactant-free” and in certain embodiments thefoamable composition is substantially free of customary surfactants, or“substantially surfactant-free”.

In the context herein, the term “substantially surfactant-freecomposition” relates to a composition that contains a total of less thanabout 0.4% of a surfactant selected from the group consisting ofcustomary non-ionic, anionic, cationic, zwitterionic, amphoteric andampholytic surfactants. Preferably, the composition comprises less thanabout 0.3% or less than about 0.2% by weight of a standard surfactantand more preferably less than about 0.1%. Where a formulation includesinsignificant amounts of surfactants it is considered to be essentiallyfree of them.

Non-surfactant or surfactant-free compositions will comprise no ornegligible levels of surface active agents.

In additional embodiments, the term “substantially surfactant-free”relates to a composition wherein the ratio between the foaming agent andthe surfactant is between 50:1 or 20:1; or between 20:1 and 10:1 orbetween 100:1 and 20:1.

In certain embodiments, the composition is free or substantially free ofan ionic surfactant. In certain embodiments, the composition is free orsubstantially free of a non-ionic surfactant.

Substantially Polymer-Free

By the term polymeric agent it is intended to mean a compound havingmultiple repeated units such as cellulose polymers, acrylic polymers,block polymers and copolymers. In one or more certain embodiments thepolymeric agent has a molecular weight of in excess of a 1000 Daltons.In one or more embodiments the formulations are substantially polymerfree. In one or more embodiments the formulations are substantiallypolymer free of a polymeric agent selected from the group consisting ofa bioadhesive agent, a gelling agent, a film forming agent and a phasechange agent, being locust bean gum, sodium alginate, sodium caseinate,egg albumin, gelatin agar, carrageenin gum, sodium alginate, xanthangum, quince seed extract, tragacanth gum, guar gum, cationic guars,hydroxypropyl guar gum, starch, amine-bearing polymers such as chitosan;acidic polymers obtainable from natural sources, such as alginic acidand hyaluronic acid; chemically modified starches and the like,carboxyvinyl polymers, polyvinylpyrrolidone, polyvinyl alcohol,polyacrylic acid polymers, polymethacrylic acid polymers, polyvinylacetate polymers, polyvinyl chloride polymers, polyvinylidene chloridepolymers, semi-synthetic polymeric materials such as cellulose ethers,such as methylcellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, hydroxyethyl cellulose, hydroxy propylmethyl cellulose,methylhydroxyethylcellulose, methylhydroxypropylcellulose,hydroxyethylcarboxymethylcellulose, carboxymethyl cellulose,carboxymethylcellulose carboxymethylhydroxyethylcellulose, and cationiccelluloses, carbomer (homopolymer of acrylic acid is crosslinked with anallyl ether pentaerythritol, an allyl ether of sucrose, or an allylether of propylene); poloxamers (synthetic block copolymer of ethyleneoxide and propylene); polyethylene glycol having molecular weight of1000 or more (e.g., PEG 1,000, PEG 4,000, PEG 6,000 and PEG 10,000) andwhich could function as a hydro alcoholic foam booster. By substantiallypolymer free it is intended to mean less than about 5%, preferably lessthan about 2%. By essentially polymer free it is intended to mean lessthan about 1%, preferably less than about 0.5%. In further embodimentsthey are essentially polymer free and in still further embodiments theyare free of polymeric agents.

In alternative embodiments the formulations may comprise a polymericagent in such case the polymeric agents are oil soluble polymericagents. Non limiting examples of oil-soluble polymeric agents are: Ethylcellulose, alkylated guar gum, trimethylsiloxysilicate, alkyl-modifiedsilicone, polyamide-modified silicone, homopolymers and copolymers ofalkyl methacrylates, alkyl acrylates, and alkyl styrenes polyisobutene,polybutyl metacrylate, polycyclohexylstyrene.

According to one or more embodiments, the composition comprises lessthan about 0.1% by weight of a polymeric agent and more preferably lessthan about 0.05%. t Polymer-free compositions will comprise no ornegligible levels of polymeric agents.

In the art, the term polymeric agent can be used loosely to refer to anypolymer. However, in some embodiments polymers that do not have a gelbuilding role but may act in other ways are not excluded from thecompositions. In one or more embodiments a polyether siloxane copolymerand a poly(dimethylsiloxane)-(diphenyl-siloxane) copolymer and the like,which can provide a good feeling to the composition are not excluded.

Physical Characteristics of the Foamable Composition and Foam

A foamable composition manufactured according to one or more embodimentsherein is very easy to use. When applied onto the afflicted body surfaceof mammals, i.e., humans or animals, it is in a foam state, allowingfree application without spillage. Upon further application of amechanical force, e.g., by rubbing the composition onto the bodysurface, it freely spreads on the surface and is rapidly absorbed.

In one or more embodiments the foamable composition is a single phasesolution. In one or more embodiments the foamable composition issubstantially a single phase solution. In certain circumstances, wherethe active agent is insoluble and is presented as a homogenoussuspension, the formulation is turbid or cloudy.

In one or more embodiments the foam composition has an acceptableshelf-life of at least six months or at least nine months or at leastone year, or of at least about one and a half years or at least twoyears at ambient temperature. A feature of a product for cosmetic ormedical use is long term stability. Propellants, which are a mixture oflow molecular weight hydrocarbons, tend to impair the stability. Thefoamable compositions herein are surprisingly stable, even in theabsence of customary surfactants and or foam adjuvants. Followingaccelerated stability studies, they demonstrate desirable texture; theyform fine bubble structures that do not break immediately upon contactwith a surface, spread easily on the treated area and absorb quickly.

The composition should also be free flowing, to allow it to flow throughthe aperture of the container, e.g., and aerosol container, and createan acceptable foam. Compositions containing a substantial amount ofsemi-solid hydrophobic solvents, e.g., white petrolatum, as the mainingredients of the oil phase of the emulsion, will likely exhibit highviscosity and poor flowability and can be inappropriate candidates for afoamable composition. Thus in one or more embodiments semi-solidhydrophobic solvents are a subsidiary component in the composition, forexample being present at less than about 25%, less than about 20%, lessthan about 15%, less than about 10%, or less than about 5% by weight ofthe foamable composition. In other embodiments they can be present inhigher amounts due to the solvent effect of the propellant diluting theformulation and enabling flowability or where the formulation ispresented as a gel or ointment.

Foam Quality

Foam quality can be graded as follows:

Grade E (excellent): very rich and creamy in appearance, does not showany bubble structure or shows a very fine (small) bubble structure; doesnot rapidly become dull; upon spreading on the skin, the foam retainsthe creaminess property and does not appear watery.

Grade G (good): rich and creamy in appearance, very small bubble size,“dulls” more rapidly than an excellent foam, retains creaminess uponspreading on the skin, and does not become watery.

Grade FG (fairly good): a moderate amount of creaminess noticeable,bubble structure is noticeable; upon spreading on the skin the productdulls rapidly and becomes somewhat lower in apparent viscosity.

Grade F (fair): very little creaminess noticeable, larger bubblestructure than a “fairly good” foam, upon spreading on the skin itbecomes thin in appearance and watery.

Grade P (poor): no creaminess noticeable, large bubble structure, andwhen spread on the skin it becomes very thin and watery in appearance.

Grade VP (very poor): dry foam, large very dull bubbles, difficult tospread on the skin.

Topically administrable foams are typically of quality grade E or G,when released from the aerosol container. Smaller bubbles are indicativeof a more stable foam, which does not collapse spontaneously immediatelyupon discharge from the container. The finer foam structure looks andfeels smoother, thus increasing its usability and appeal.

Foam Density

Another property of the foam is specific gravity or density, as measuredupon release from the aerosol can. Typically, foams have specificgravity of less than 0.50 g/mL or less than 0.12 g/mL, depending ontheir composition and on the propellant concentration. In one or moreembodiments the foam density is about less than 0.3 g/mL or is aboutless than 0.2 g/mL; or is about less than 0.1 g/mL or is about less than0.05 g/mL.

Shakability

‘Shakability’ means that the composition contains some or sufficientflow to allow the composition to be mixed or remixed on shaking That is,it has fluid or semi fluid properties. Shakability is described furtherin examples in Tests section. In one or more certain limited embodimentsthe formulation is poorly shakable but is nevertheless flowable.

Breakability/Collapse Time

A further aspect of the foam is breakability. The balance betweenstability and breakability of the foam coming out of the container isvery delicate: on the one hand the foam should preferably not be “quickbreaking”, i.e., it should be stable upon release from the pressurizedcontainer and not break as a result of exposure to skin temperature; andon the other hand, it should be “breakable”, i.e., it should spreadeasily, break down and absorb into the skin or membrane upon applicationof mild shear force. The breakable foam is thermally stable, yet breaksunder shear force. Shear-force breakability of the foam is clearlyadvantageous over thermally-induced breakability. Thermally sensitivefoams start to collapse immediately upon exposure to skin temperatureand, therefore, cannot be applied on the hand and afterwards deliveredto the afflicted area.

The collapse time of foam represents its tendency to betemperature-sensitive and its ability to be at least stable in the shortterm so as to allow a user sufficient time to comfortably handle andapply the foam to a target area without being rushed and or concernedthat it may rapidly collapse, liquefy and or disappear. Collapse time,as an indicator of thermal sensitivity, is examined by dispensing agiven quantity of foam and photographing sequentially its appearancewith time during incubation at 36° C. (the procedure is explained infurther detail in the Examples). The collapse time result is defined asthe time when the foam reaches 50% of its initial height. Foams whichare structurally stable on the skin and have not reached 50% of theirinitial height after at least one minute are termed “short term stable”carriers or foams. Simple collapse time can be measured by applying afoam sample on a body surface like the fingers at normal bodytemperature of about 37° C.

Oils may cause foam to be thermolabile and “quick breaking” However, incertain embodiments herein, despite the presence of high oil content,quite unexpectedly the foam is substantially thermally stable. By“substantially thermally stable” it is meant that the foam uponapplication onto a warm skin or body surface at about 35-37° C. it doesnot collapse within about 30 seconds. Thus, in one or more embodimentsthe simple collapse time of the foam is more than about 30 seconds ormore than about one minute or more than about two minutes. In one ormore limited embodiments simple collapse time can be a little shorterthan 30 seconds, but not less than about 20 seconds. In one or furtheror alternative embodiments the collapse time is measured by introducinga sample of foam into an incubator at 36° C. and the collapse time ofthe foam is more than 30 seconds or more than about one minute or morethan about two minutes.

Pharmaceutical Composition

The foamable oleaginous composition of the present invention can be usedby itself as a topical treatment of a body surface, as many hydrophobicsolvents such as emollients, unsaturated oils, essential oils ortherapeutic oils that possess cosmetic or medical beneficial effects.Furthermore, it is an ideal vehicle for active pharmaceuticalingredients and active cosmetic ingredients. In the context activepharmaceutical ingredients and active cosmetic ingredients arecollectively termed “active agent” or “active agents”. The absence ofsurfactants in the composition is especially advantageous, since nosurfactant-related adverse reactions are expected from such acomposition. Some surfactants may act to facilitate gelling of thepre-foam formulation. The absence of such surfactants may avoid thisundesirable phenomenon. In one or more embodiments the active agent issoluble in the composition of a phase thereof. In one or more otherembodiments it is partially soluble or insoluble. When partially solubleor insoluble the active agent is presented as a suspension or it can beencapsulated in a carrier.

Whilst some active ingredients are effectively inert in the wax/solventcompositions described herein other active ingredients are verysensitive to degradation and can react, break down or rearrange readily.For example, tetracycline antibiotics such as minocycline or doxycyclinebreak down upon being exposed to many excipients as disclosed in thestudy described in Example 9. Thus, in one or more embodiments an activeagent is first tested for compatibility with each of the formulationingredients. In one or more embodiments the active agent is compatiblewith the other ingredients.

Suitable active agents include but are not limited to an active herbalextract, an acaricides, an age spot and keratose removing agent, anallergen, an alpha hydroxyl acid, an analgesic agent, an androgen, anantiacne agent, an antiallergic agent, an antiaging agent, anantibacterial agent, an antibiotic, an antiburn agent, an anticanceragent, an antidandruff agent, an antidepressant, an antidermatitisagent, an antiedemic anent, an antifungal agent, an antihistamine, anantihelminth agent, an anti-hyperkeratosis agent, an anti-infectiveagent, an antiinflammatory agent, an antiirritant, an antilipemic agent,an antimicrobial agent, an antimycotic agent, an antioxidant, anantiparasitic agent, an antiproliferative agent, an antipruritic agent,an antipsoriatic agent, an antirosacea agent, an antiseborrheic agent,an antiseptic agent, an antiswelling agent, an antiviral agent, ananti-wart agent, an anti-wrinkle agent, an anti-yeast agent, anastringent, a beta-hydroxy acid, benzoyl peroxide, a cardiovascularagent, a chemotherapeutic agent, a corticosteroid, an immunogenicsubstance, a dicarboxylic acid, a disinfectant, an estrogen, afungicide, a hair growth regulator, a haptene, a hormone, a hydroxyacid, an immunosuppressant, an immunoregulating agent, animmunomodulator, an immunostimulant, an insecticide, an insectrepellent, a keratolytic agent, a lactam, a local anesthetic agent, alubricating agent, a masking agent, a metal, a metal oxide, a mitocide,a neuropeptide, a non-steroidal anti-inflammatory agent, an oxidizingagent, a pediculicide, a peptide, a pesticide, a progesterone, aprotein, a photodynamic therapy agent, a radical scavenger, a refattingagent, a retinoid, a sedative agent, a scabicide, a self tanning agent,a skin protective agent, a skin whitening agent, a steroid, a steroidhormone, a vasoactive agent, a vasoconstrictor, a vasodilator, avitamin, a vitamin A, a vitamin A derivative, a vitamin B, a vitamin Bderivative, a vitamin C, a vitamin C derivative, a vitamin D, a vitaminD derivative, a vitamin D analog, a vitamin F, a vitamin F derivative, avitamin K, a vitamin K derivative, a wound healing agent and a wartremover. As is known to one skilled in the art, in some instances aspecific active agent may have more than one activity, function oreffect.

Encapsulation of an Active Agent

In one or more embodiments, the active agent is encapsulated inparticles, microparticles, nanoparticles, microcapsules, microspheres,nanocapsules, nanospheres, liposomes, niosomes, polymer matrix,silica-gel, graphite, nanocrystals or microsponges. Such particles canhave various functions, such as (1) protection of the drug fromdegradation; (2) modification of the drug release rate from thecomposition; (3) control of skin penetration profile; and (4) mitigationof adverse effects, due to the controlled release of the active agentfrom the encapsulation particles.

Solubility of an Active Agent

Solubility of the steroid is an important factor in the development of astable foamable composition according to the present invention.

For definition purposes, in the context of the present invention, thedescriptive terminology for solubility according to the US Pharmacopoeia(USP 23, 1995, p. 10), the European Pharmacopoeia (EP, 5^(th) Edition(2004), page 7) and several other textbooks used in the art ofpharmaceutical sciences (see for example, Martindale, The ExtraPharmacopoeia, 30^(th) Edition (1993), page xiv of the Preface; andRemington's Pharmaceutical Sciences, 18^(th) Edition (1990), page 208)is adapted:

Parts of Solvent Required Descriptive Term for 1 Part of Solute Verysoluble Less than 1 Freely soluble From 1 to 10 Soluble From 10 to 30Sparingly soluble From 30 to 100 Slightly soluble From 100 to 1,000 Veryslightly soluble From 1,000 to 10,000 Practically insoluble or Insoluble10,000 and over

Thus, in one or more embodiments, the active agent is “soluble”, “freelysoluble” or “very soluble” (as defined above) in the composition. Yet,in certain cases, the active agent is “very slightly soluble”, “slightlysoluble” or “sparingly soluble” in the composition.

Yet, in one or more embodiments, the active agent is insoluble i.e.,“requires 10,000 parts or more of a solvent to be solubilized”, in thecomposition.

In certain embodiments it is desirable that the active agent ismaximally soluble in the composition, because solubility of the activeagents is expected to increase its bioavailability.

Yet, in additional embodiments it is desirable that the active agent isinsoluble in the composition, because its degradation is enhanced whenit is dissolved. In such cases, the hydrophobic solvent is selected by(1) testing the solubility of said active agent in various hydrophobicsolvents, followed by (2) inclusion in the composition of such solventsthat do not solubilize the active agent. In one or more embodiments theactive agent is presented as a suspension. In one or more furtherembodiments the active agent is micronized, which can assist in deliveryinto the skin, mucosal membrane and body cavity surfaces and also aidhomogenous distribution within the formulation.

Exemplary Groups of Active Agents

Antibiotics

In the context of the present disclosure, an antibiotic agent is asubstance, that has the capacity to inhibit the growth of or to destroybacteria and other microorganisms.

In one or more embodiments, the antibiotic agent is selected from theclasses consisting beta-lactam antibiotics, aminoglycosides, ansa-typeantibiotics, anthraquinones, antibiotic azoles, antibioticglycopeptides, macrolides, antibiotic nucleosides, antibiotic peptides,antibiotic polyenes, antibiotic polyethers, quinolones, antibioticsteroides, sulfonamides, tetracycline, dicarboxylic acids, antibioticmetals including antibiotic metal ions, oxidizing agents, a periodate, ahypochlorite, a permanganate, substances that release free radicalsand/or active oxygen, cationic antimicrobial agents, quaternary ammoniumcompounds, biguanides, triguanides, bisbiguanides and analogs andpolymers thereof, naturally occurring antibiotic compounds, includingantibiotic plant oils and antibiotic plant extracts and any one of thefollowing antibiotic compounds including non classified antibioticcompound analogs, derivatives, salts, ions, complexes and mixturesthereof.

Tetracyclines

According to some embodiments, the antibiotic agent is a tetracycline.The tetracyclines (also referred to herein as “tetracyclineantibiotics”) are a group of antibacterials, originally derived fromcertain Streptomyces spp., having the same tetracyclic nucleus,naphthacene, and similar properties. They are usually bacteriostatic butact by interfering with protein synthesis in susceptible organisms.Tetracycline antibiotics are susceptible to degradation by oxidation.

Tetracyclines include, but are not limited to, dihydrosteffimycin,demethyltetracycline, aclacinomycin, akrobomycin, baumycin,bromotetracycline, cetocyclin, chlortetracycline, clomocycline,daunorubicin, demeclocycline, doxorubicin, doxorubicin hydrochloride,doxycycline, lymecyclin, marcellomycin, meclocycline, meclocyclinesulfosalicylate, methacycline, minocycline, minocycline hydrochloride,musettamycin, oxytetracycline, rhodirubin, rolitetracycline, rubomycin,serirubicin, steffimycin, tetracycline and analogs, salts andderivatives thereof.

Chlortetracycline, oxytetracycline, tetracycline, demeclocycline are allnatural products that have been isolated from Streptomyces spp. The morerecent tetracyclines, namely methacycline, doxycycline, and minocycline,are semisynthetic derivatives. Methacycline, like demeclocycline, has alonger half-life than tetracycline. Minocycline is active against sometetracycline-resistant bacteria, including strains of staphylococci.Both doxycycline and minocycline are more lipid-soluble than the othertetracyclines and they penetrate well into tissues. They are thus moresuitable for incorporating into oily or emollient containingformulations. However, they have a place in the treatment of chlamydialinfections, rickettsial infections such as typhus and the spottedfevers, mycoplasmal infections such as atypical pneumonia, pelvicinflammatory disease, Lyme disease, brucellosis, tularaemia, plague,cholera, periodontal disease, and acne. The tetracyclines have also beenuseful in the treatment of penicillin-allergic patients suffering fromvenereal diseases, actinomycosis, bronchitis, and leptospirosis.Minocycline may sometimes be used in multidrug regimens for leprosy.Doxycycline may be used for the treatment and prophylaxis of malaria; itis also used in the management of anthrax.

In an embodiment the active ingredient may be any one of the followingnon limiting examples chlortetracycline, demeclocycline, doxycycline,lymecycline, meclocycline, methacycline, minocycline, oxytetracycline,rolitetracycline, tetracycline. In a preferred embodiment they aredoxycycline or minocycline.

Tetracycline antibiotics can be incorporated into the formulations ofthe present invention to treat, ameliorate or prevent a multitude ofdisorders responsive to tetracycline antibiotics. The formulations canbe applied topically to the skin or to the genitals or to mucosalmembranes and on and around the eye, sub-gingival and can be appliedinto a wide range of body cavities, including aural, digestive, oral,nasal, urethra, penal, endocervical, rectum, respiratory, and vaginaland tooth pocket. Non limiting examples of applications include eyeinfections, blepharitis, dry eye, inclusion conjunctivitis, glaucoma,inflammatory ocular conditions where bacterial infection or a risk ofbacterial ocular infection exists, neuropathic atrophy (in diabetes),abrasions, injuries, wounds, burns, ulcers, pyoderma, furunculosis,granuloma inguinale, periodontitis, rosacea, post-operation infectionsand tissue reconstruction, trachoma, lymphogranuloma venereum, granulomainquinale, acne, inflammation, sinusitis, neuro-protection, washing out,disinfectation, and stabilization of body cavities, at on around or inthe site of an operation, which for example can provide multipletherapeutic effects, such as, inhibition of post operation adhesions,anti infection, neuro-protection.

Whether delivered as a foam, gel, ointment or suspension the activepharmaceutical tetracycline can be present by weight in the range ofabout 0.2% to about 20%, or at about 0.2%, at about 0.3%, at about 0.4%,at about 0.5%, at about 0.6%, at about 0.7%, at about 0.8%, at about0.9%, at about 1%, at about 1.5%, at about 2%, at about 2.5%, at about3%, at about 3.5% at about 4%, at about 4.5%, at about 5%, at about 6%,at about 7%, at about 8%, at about 9%, at about 10%, at about 12%, or atabout 14%, at about 16%, at about 18%, or at about 20%.

Tetracyclines and Skin Infections

Tetracyclines have been used in ophthalmic ointments for the preventionor treatment of infections of the eye caused by susceptible bacteria.Although minor skin infections and wounds usually heal withouttreatment, some minor skin wounds do not heal without therapy and it isimpossible to determine at the time of injury which wounds will beself-healing. Therefore, some experts believe that, by reducing thenumber of superficial bacteria, topical anti-infectives are useful forpreventing infection in minor skin injuries (e.g., cuts, scrapes,burns).

Tetracycline hydrochloride may be used topically in the treatment ofinflammatory acne vulgaris. Tetracyclines are usually bacteriostatic inaction, but may be bactericidal in high concentrations or against highlysusceptible organisms.

Tetracyclines appear to inhibit protein synthesis in susceptibleorganisms primarily by reversibly binding to 30S ribosomal subunits,thereby inhibiting binding of aminoacyl transfer-RNA to those ribosomes.In addition, tetracyclines appear to reversibly bind to 50S ribosomalsubunits. There is preliminary evidence that tetracyclines also altercytoplasmic membranes of susceptible organisms resulting in leakage ofnucleotides and other intracellular components from the cell. At highconcentrations, tetracyclines also inhibit mammalian protein synthesis.

The exact mechanisms by which tetracyclines reduce lesions of acnevulgaris have not been fully elucidated; however, the effect appears tobe partly the result of the antibacterial activity of the drugs.Following topical application to the skin of a 0.22% solution oftetracycline hydrochloride in a vehicle containing n-decyl methylsulfoxide (Topicycline®; no longer commercially available in the US),the drug inhibits the growth of susceptible organisms (principallyPropionibacterium acnes) on the surface of the skin and reduces theconcentration of free fatty acids in sebum. The reduction in free fattyacids in sebum may be an indirect result of the inhibition oflipase-producing organisms which convert triglycerides into free fattyacids or may be a direct result of interference with lipase productionin these organisms. Free fatty acids are comedogenic and are believed tobe a possible cause of the inflammatory lesions (e.g., papules,pustules, nodules, cysts) of acne. However, other mechanisms also appearto be involved because clinical improvement of acne vulgaris withtopical tetracyclines does not necessarily correspond with a reductionin the bacterial flora of the skin or a decrease in the free fatty acidcontent of sebum. (Martindale Electronic Version 2007).

Tetracyclines, Solubility and Stability

Tetracyclines are known to be unstable in the presence of water, as wellas numerous types of formulation excipients, such as protic solvents,various surfactants and certain oils. We surprisingly discovered thatthe inclusion of tetracyclines in a composition comprising a hydrophobicsolvent and a foaming agent described herein results in a stableproduct, with extended stability of the tetracycline. In an embodiment ahydrophobic solvent is selected by (1) testing the solubility of saidactive agent in various hydrophobic solvents, (2) identifying those thatdo not solubilize the active agent followed by (3) inclusion in thecomposition of such solvents that do not solubilize the active agent. Incertain embodiments the tetracycline is insoluble in the composition.

Doxycycline

According to some embodiments, the tetracycline is doxycycline.Doxycycline is a tetracycline antibiotic and also has anti-inflammatoryand immunomodulatory effects. Doxycycline is a semisynthetictetracycline antibiotic derived from oxytetracycline. In addition toantimicrobial activity, the drug has anti-inflammatory andimmunomodulatory effects. It is available as Doxycycline calcium,doxycycline hyclate and doxycycline monohydrate. Doxycycline hyclate anddoxycycline monohydrate occur as yellow, crystalline powders. Thehyclate is soluble in water and slightly soluble in alcohol; themonohydrate is very slightly soluble in water and sparingly soluble inalcohol. Doxycycline calcium is formed in situ during the manufacturingprocess. Following reconstitution of doxycycline hyclate powder for IVadministration with sterile water for injection, solutions have a pH of1.8-3.3.

The mechanism(s) by which doxycycline reduces inflammatory lesions(papules and pustules) in patients has not been elucidated, but theseeffects may result at least in part from the anti-inflammatory actionsof the drug; other mechanisms may be involved

Doxycycline is used for the treatment of rosacea treatment orprophylaxis of anthrax (including inhalational anthrax [postexposure]),treatment of presumed or confirmed rickettsial infections, includingRocky Mountain spotted fever (RMSF), fever, ehrlichiosis, andanaplasmosis, and for the treatment of Bartonella infections, for thetreatment of brucellosis, for the treatment of Burkholderia Infections,Chlamydial Infections, Lymphogranuloma venereum Psittacosis,Ehrlichiosis and Anaplasmosis, Gonorrhea and Associated Infections,Epididymitis, Proctitis, Granuloma Inguinale (Donovanosis,) LegionellaInfections, Leptospirosis, Lyme Disease, Prophylaxis of Lyme Disease,Erythema Migrans, Early Neurologic Lyme Disease, Lyme Carditis, orBorrelial Lymphocytoma, Lyme Arthritis, Malaria, and prevention,Mycobacterial Infections, Mycobacterium marinum Infections, PelvicInflammatory Disease, Parenteral Regimens, Plague, pleural Effusion,Rickettsial Infections, Q Fever, Syphilis, Tularemia, Treatment,Postexposure Prophylaxis

When reconstituted and diluted with 0.9% sodium chloride or 5% dextrose,doxycycline hyclate IV solutions containing 0.1-1 mg of doxycycline permL are stable for 48 hours at 25° C.; when reconstituted and dilutedwith Ringer's, 10% invert sugar, Normosol-M® in D5W, Normosol-R® in D5W,Plasma-Lyte® 56 in 5% dextrose, or Plasma-Lyte® 148 in 5% dextrose,doxycycline hyclate IV solutions containing 0.1-1 mg/mL are stable for12 hours at room temperature. The manufacturer states that doxycyclinehyclate solutions prepared with any of these infusion solutions arestable for 72 hours at 2-8° C. when protected from direct sunlight andartificial light; however, after storage in this manner, infusion ofthese solutions must be completed within 12 hours Doxycycline hyclate IVsolutions diluted to a concentration of 0.1-1 mg/mL with lactatedRinger's injection or 5% dextrose in lactated Ringer's injection must beinfused within 6 hours to ensure stability. During infusion, alldoxycycline hyclate IV solutions must be protected from direct sunlight.(Martindale 2007 Electronic Version). Thus it can be seen thatDoxycycline is not stable for more than short periods of a matter ofhours.

Preparations of doxycycline hyclate have an acid pH and incompatibilitymay reasonably be expected with alkaline preparations or with drugsunstable at low pH.

Doxycycline is more active than tetracycline against many bacterialspecies including Streptococcus pyogenes, enterococci, Nocardia spp.,and various anaerobes. Cross-resistance is common although sometetracycline-resistant Staphylococcus aureus respond to doxycycline.Doxycycline is also more active against protozoa, particularlyPlasmodium spp.

Doxycycline is a tetracycline derivative with uses similar to those oftetracycline. It may sometimes be preferred to other tetracyclines inthe treatment of susceptible infections because of its fairly reliableabsorption and its long half-life that permits less frequent (often oncedaily) dosing. It also has the advantage that it can be given (withcare) to patients with renal impairment. However, relatively high dosesmay need to be given for urinary-tract infections because of its lowrenal excretion.

For relapsing fever and louse-borne typhus, for the prophylaxis ofleptospirosis, for periodontiti, for Lymphatic filariasis, forMusculoskeletal and joint disorders and for the treatment of acne.

Minocycline

According to some embodiments, the tetracycline is minocycline.Minocycline hydrochloride is a semisynthetic tetracycline antibioticderived from tetracycline. The drug is usually bacteriostatic in action;it exerts its antimicrobial activity by inhibiting protein synthesis. Itis a yellow crystalline powder that is sparingly soluble in water;slightly soluble in alcohol; practically insoluble in chloroform and inether; soluble in solutions of alkali hydroxides and carbonates. pH of asolution in water containing the equivalent of minocycline 1% is between3.5 and 4.5. Preparations of minocycline hydrochloride have an acid pHand incompatibility may reasonably be expected with alkalinepreparations or with drugs unstable at low pH.

Minocycle is highly sensitive and should be stored in airtightcontainers and protected from light to prevent degradation. Thereforeuse in foamable formulations stored in airtight sealed containers underpressure with propellant may contribute to preserving stability subjectto selection of compatible canisters and accessories.

Photosensitivity, manifested as an exaggerated sunburn reaction on areasof the body exposed to direct sunlight or ultraviolet light, hasoccurred with tetracyclines and Minocycline has been associated withpigmentation of the skin and other tissues.

Minocycline has a spectrum of activity and mode of action similar tothat of tetracycline but it is more active against many speciesincluding Staphylococcus aureus, streptococci, Neisseria meningitidis,various enterobacteria, Acinetobacter, Bacteroides, Haemophilus,Nocardia, and some mycobacteria, including M. leprae. Partialcross-resistance exists between minocycline and other tetracyclines butsome strains resistant to other drugs of the group remain sensitive tominocycline, perhaps because of better cell-wall penetration.Minocycline is a tetracycline derivative with uses similar to those oftetracycline. It is also a component of multidrug regimens for thetreatment of leprosy and has been used in the prophylaxis ofmeningococcal infection to eliminate the carrier state, but the highincidence of vestibular disturbances means that it is not the drug ofchoice for the latter. It has neuroprotective properties. It is beinginvestigated for motor neurone disease, for the management ofHuntington's chorea. It is used in the treatment of rheumatoid arthritisand in the treatment of various skin disorders, including acne.

Steroids

In an embodiment, the active agent is a steroid. In certain embodimentsthe steroid is a corticosteroid, including but not limited to,hydrocortisone, hydroxyltriamcinolone, alpha-methyl dexamethasone,dexamethasone-phosphate, beclomethsone dipropionate, clobetasolvalemate, desonide, desoxymethasone, desoxycorticosterone acetate,dexamethasone, dichlorisone, diflorasone diacetate, diflucortolonevalerate, fluadrenolone, fluclorolone acetonide, fludrocortisone,flumethasone pivalate, fluosinolone acetonide, fluocinonide, flucortinebutylester, fluocortolone, fluprednidene (fluprednylidene) acetate,flurandrenolone, halcinonide, hydrocortisone acetate, hydrocortisonebutyrate, methylprednisolone, triamcinolone acetonide, cortisone,cortodoxone, flucetonide, fludrocortisone, difluorosone diacetate,fluradrenolone acetonide, medrysone, amcinafel, amcinafide,betamethasone and the balance of its esters, chloroprednisone,chlorprednisone acetate, clocortelone, clescinolone, dichlorisone,difluprednate, flucloronide, flunisolide, fluoromethalone, fluperolone,fluprednisolone, hydrocortisone valerate, hydrocortisonecyclopentylpropionate, hydrocortmate, mepreddisone, paramethasone,prednisolone, prednisone, beclomethasone dipropionate, triamcinolone, aswell as analogs, derivatives, salts, ions and complexes thereof.

In certain embodiments, the steroid is a hormone or a vitamin, asexemplified by pregnane, cholestane, ergostane, aldosterone,androsterone, calcidiol, calciol, calcitriol, calcipotriol,clomegestone, cholesterol, corticosterone, cortisol, cortisone,dihydrotestosterone, ergosterol, estradiol, estriol, estrone,ethinylestradiol, fusidic acid, lanosterol, prednisolone, prednisone,progesterone, spironolactone, timobesone and testosterone, as well asanalogs, derivatives, salts, ions and complexes thereof. For substanceslike calcitriol, very low amounts such as about 0.0001% to about 0.005%by weight of foam formulation or gel or ointment or suspension, or about0.0001%, about 0.0002%, about 0.0003%, about 0.0004%, about 0.0005%,about 0.0006%, about 0.0007%, about 0.0008%, about 0.0009%, about0.001%, about 0.0011%, about 0.0012%, about 0.0013%, about 0.0014%,about 0.0015%, about 0.0016%, about 0.0017%, about 0.0018%, about0.0019%, about 0.002%, about 0.003%, about 0.004%, about 0.005% byweight are effective. In some embodiments the active pharmaceuticalagent is delivered by more than one route, for example, topically andbody cavity.

In an embodiment, the steroid is mometasone furoate. In certainembodiments it can be used topically to treat psoriasis and dermatitis.In certain other embodiments it can be applied in nasal administrationto treat disorders, such as, allergic rhinitis and asthma.

NSAID

In an embodiment, the active agent is a non-steroidal anti-inflammatoryagent. In the context a nonsteroidal antiinflammatory agent (also termedherein “NSAID”) is a pharmaceutically active compound, other than acorticosteroid, which affects the immune system in a fashion thatresults in a reduction, inhibition, prevention, amelioration orprevention of an inflammatory process and/or the symptoms ofinflammation and or the production pro-inflammatory cytokines and otherpro-inflammatory mediators, thereby treating or preventing a diseasethat involves inflammation.

In one or more embodiments, the NSAID is an inhibitor of thecyclooxygenase (COX) enzyme. Two forms of cyclooxygenase are knowntoday: the constitutive cyclooxygenase (COX-1); and the induciblecyclooxygenase (COX-2), which is pro-inflammatory. Thus, in one or moreembodiments, the NSAID is selected from the group consisting of a COX-1inhibitor, a COX-2 inhibitor or a non-selective NSAID, whichsimultaneously inhibits both COX-1 and COX-2.

In one or more embodiments, the NSAID is salicylic acid a salicylic acidderivatives. Exemplary salicylic acid derivative include, in a nonlimiting fashion, aspirin, sodium salicylate, choline magnesiumtrislicylate, salsalate, diflunisal, salicylsalicylic acid,sulfasalazine, olsalazine, esters of salicylic acid with a carboxylicacid, esters of salicylic acid with a dicarboxylic acid, esters ofsalicylic acid with a fatty acid, esters of salicylic acid with ahydroxyl fatty acid, esters of salicylic acid with an essential fattyacid, esters of salicylic acid with a polycarboxylic acid, and anycompound wherein salicylic acid is linked to an organic moiety through acovalent bond.

In one or more embodiments, the NSAID is para-aminophenol (e.g.,acetaminophen) and salts and derivatives thereof.

In one or more embodiments, the NSAID is an indole or an indole-aceticacid derivative (e.g., indomethacin, sulindac, etodolac) and salts andderivatives thereof.

In one or more embodiments, the NSAID is an aryl acetic acids (e.g.,tolmetin, diclofenac, ketorolac) and salts and derivatives thereof.

In one or more embodiments, the NSAID is an arylpropionic acid and saltsand derivatives thereof. Exemplary arylpropionic acid derivativeinclude, in a non limiting fashion, are ibuprofen, naproxen,flubiprofen, ketoprofen, fenoprofen, oxaprozin.

In one or more embodiments, the NSAID is anthranilic acids or ananthranilic acid derivative, also termed “fenamates” (e.g., mefenamicacid, meclofenamic acid) and salts and derivatives thereof.

In one or more embodiments, the NSAID is selected from the group ofenolic acids, enolic acid salts, enolic acid esters, amides, anhydridesand salts and derivatives thereof. Non-limiting examples of enolic acidderivatives include oxicams (piroxicam, tenoxicam) andpyrazolidinediones (phenylbutazone, oxyphenthratrazone)

Yet, in additional embodiments, the NSAID is an alkanone (e.g.,nabumetone).

Selective COX-2 Inhibitors include, in an exemplary mannerdiaryl-substituted furanones (e.g., Rofecoxib); diaryl-substitutedpyrazoles (e.g., Celecoxib); indole acetic acids (e.g., Etodolac); andsulfonanilides (e.g., Nimesulide) and salts and derivatives thereof.

Local Anesthetic Agents

In an embodiment, the active agent is a local anesthetic agent. Withoutlimiting the scope, the anesthetic agent can be selected from the groupconsisting of benzocaine, lidocaine, bupivacaine, chlorprocaine,dibucaine, etidocaine, mepivacaine, tetracaine, dyclonine, hexylcaine,procaine, cocaine, ketamine, pramoxine, phenol, any pharmaceuticallyacceptable salts thereof and mixtures of such anesthetic agents. Anymixture of synergistically beneficial anesthetic agents is contemplated.

Keratolytically Active Agents

A keratolytic agent may be included as an active agent of a foamablecomposition. The term “keratolytically active agent” as used hereinincludes a compound that loosens and removes the stratum corneum of theskin, or alters the structure of the keratin layers of skin.Keratolytically active agents are used in the treatment ofdermatological disorders that involve dry skin, hyperkeratinization(such as psoriasis), skin itching (such as xerosis), acne and rosacea.

Suitable keratolytically active agents include phenol and substitutedphenolic compounds. Such compounds are known to dissolve and loosen theintracellular matrix of the hyperkeratinized tissue. As such, they areused in the treatment of dermatological disorders. Dihydroxybenzene andderivatives thereof have been recognized as potent keratolytic agents.Resorcinol (m-dihydroxybenzene) and derivatives thereof are used inanti-acne preparations. In addition to hydroquinone (p-dihydroxybenzene)having anti-pigmentation properties, hydroquinone is also known to bekeratolytic. These compounds also exhibit antiseptic properties. Cresolsalso possess bactericidal and keratolytic properties.

Vitamin A and vitamin A derivatives, also termed herein “retinoids”,such as retinoic acid, isoretinoic acid, retinol and retinal, as well asadapalene, tazarotene, isotretinoin, acitretin and additional retinoidsknown in the art of pharmaceuticals and cosmetics are another class ofkeratolytically active agents.

Another group of keratolytically active agents include alpha-hydroxyacids, such as lactic acid and glycolic acid and their respective saltsand derivatives; and beta-hydroxy acids, such as salicylic acid(o-hydroxybenzoic acid) and salicylic acid salts and pharmaceuticallyacceptable derivatives.

Another class of keratolytically active agents includes urea and ureaderivatives.

Immunomodulators

In an embodiment, the active agent is an immunomodulator.Immunomodulators are chemically or biologically-derived agents thatmodify the immune response or the functioning of the immune system.Immunomodulators suitable for use according to the present inventioninclude, among other options, cyclic peptides, such as cyclosporine,tacrolimus, tresperimus, pimecrolimus, sirolimus, verolimus, laflunimus,laquinimod and imiquimod, as well as analogs, derivatives, salts, ionsand complexes thereof. Such compounds, delivered in the foam, areespecially advantageous in skin disorders such as psoriasis, eczema andatopic dermatitis, where the large skin areas are to be treated.

Retinoids

In an embodiment, the active agent is a retinoid. Retinoids suitable foruse according to the present invention include, among other options,retinol, retinal, retinoic acid, isotretinoin, tazarotene, adapalene,13-cis-retinoic acid, acitretin all-trans beta carotene, alpha carotene,lycopene, 9-cis-beta-carotene, lutein and zeaxanthin, as well as anyadditional retinoids known in the art of pharmaceuticals and cosmetics;and analogs, derivatives, salts, ions and complexes thereof.

Anti-Acne and Anti-Rosacea Active Agents

In an embodiment, the active agent is an anti-acne or an anti-rosaceaagent. The anti-acne agent can be selected from the group consisting ofresorcinol, sulfur, salicylic acid and salicylates, alpha-hydroxy acids,nonsteroidal anti-inflammatory agents, benzoyl peroxide, retinoic acid,isoretinoic acid and other retinoid compounds, adapalene, tazarotene,azelaic acid and azelaic acid derivatives, antibiotic agents, such aserythromycin and clyndamycin, coal tar, zinc salts and complexes, andcombinations thereof, in a therapeutically effective concentration.

Antipsoriasis Agents

In an embodiment, the active agent is an anti-psoriasis agent. Suchanti-psoriasis agents can be selected, among other options, from thegroup of keratolytically-active agents, salicylic acid, coal tar,anthralin, corticosteroids, vitamin D and derivatives and analogsthereof, including vitamin D3 analogs such as calcitriol, calcipotriol;retinoids, and photodymamic therapy agents.

Antiinfective Agents

In an embodiment, the active agent is an anti-infective agent. Suchanti-infective agent can be selected from the group of an antibioticagent, an antibacterial agent, an antifungal agent, an agent thatcontrols yeast, an antiviral agent and an antiparasitic agent. Exemplaryantiinfective agents are exemplified by beta-lactam antibiotic, anaminoglycoside, an ansa-type antibiotic, an anthraquinone, an azole,metronidazole, an antibiotic glycopeptide, a macrolide, erythromycin,clindamycin, an antibiotic nucleoside, an antibiotic peptide, polymyxinB, an antibiotic polyene, an antibiotic polyether, an antibioticquinolone, an antibiotic steroid, fucidic acid, mupirocin,chloramphenicol, a sulfonamide, tetracycline, an antibiotic metal,silver, copper, zinc, mercury, tin, lead, bismuth, cadmium, chromium, anoxidizing agent, iodine, iodate, a periodate, a hypochlorite, apermanganate, a substance that release free radicals and/or activeoxygen, a cationic antimicrobial agent, a quaternary ammonium compound,a biguanide, chlorohexidine, a triguanide, a bisbiguanide, a polymericbiguanide and a naturally occurring antibiotic compound, as well asanalogs, derivatives, salts, ions and complexes thereof.

The Foamable Composition Essential Ingredients as Active Agents

In certain embodiments, a hydrophobic solvent possesses therapeuticproperties on its own and therefore, it can be regarded as “activeagent.” For example, some essential oils kill microorganisms and can beeffective in the treatment or prevention of conditions that involvemicrobial infection, such as bacterial, fungal and viral conditions.Additionally, the occlusive effect of hydrophobic solvents is useful forthe treatment of conditions which involve damaged skin, such aspsoriasis or atopic dermatitis. The combination of a hydrophobic solventand a therapeutically effective fatty alcohol or fatty acid may afford asynergistic beneficial effect in conditions characterized, for example,by infection and/or inflammation.

Combination of Active Agents

Several disorders involve a combination of more than one etiologicalfactor; and therefore, the use of more that one active agents isadvantageous. For example, psoriasis involves excessive cellproliferation and inadequate cell differentiation as well asinflammation. Atopic dermatitis involves keratinocyte growthabnormality, skin dryness and inflammation. Bacterial, fungal and viralinfections involve pathogen colonization at the affected site andinflammation. Hence, in many cases, the inclusion of a combination ofactive agents in the foamable pharmaceutical composition can bedesirable. Thus, in one or more embodiments, the foamable compositionfurther includes at least two active agents, in a therapeuticallyeffective concentration.

In an embodiment one of the active agents is a vitamin, a vitaminderivative or analogue thereof. In a preferred embodiment the vitamin,vitamin derivative or analogue thereof is oil soluble.

Microsponges

Microsponges (or microspheres) are rigid, porous and spongelike roundmicroscopic particles of cross-linked polymer beads (e.g., polystyreneor copolymers thereof), each defining a substantially noncollapsiblepore network. Microsponges can be loaded with an active ingredient andcan provide a controlled time release of the active ingredient to skinor to a mucosal membrane upon application of the formulation. The slowrelease is intended to reduce irritation by the active ingredient.Microsponge® delivery technology was developed by Advanced PolymerSystems. In one or more embodiments the composition comprises one ormore active agents loaded into Microponges with a waterless carrierdescribed herein, which may also comprise a modulating agent.

Fields of Applications

The foamable carrier of the present disclosure is suitable for treatingany inflicted surface. In one or more embodiments, foamable carrier issuitable for administration to the skin, a body surface, a body cavityor mucosal surface, e.g., the cavity and/or the mucosa of the nose,mouth, eye, respiratory system, vagina, urethra, rectum and the earcanal (severally and interchangeably termed herein “target site”).

The foamable carrier of the present disclosure is also suitable forpreventing a disorder or disease prior to its onset. The foamble carriercomprising for example a tetracycline may be applied to a body surfaceor a body cavity to try and prevent apoptosis, a disorder or diseaseprior to onset thereof. For example, prior to an anticipatedinflammatory reaction or risk thereof, or prior to an anticipated onsetof apoptosis or a risk thereof, or prior to an anticipated onset ofinflammatory cytokines or risk thereof, prior to a medical procedurerequiring intervention such as chemo therapy; radiotherapy, photodynamictherapy, laser therapy, etc. An simple example of prevention use, suchas in the case of an eye infection say of one eye, is where the foamcomprising a tetracycline (or the formulation prior to addition ofpropellant) is applied to the skin surface surrounding both eyes so asto reduce the risk of the infection spreading to the second eye oralternatively or additionally to the eye itself.

According to another embodiment a none limiting list of disorders wherea tetracycline antibiotic might be used to prevent a disease or disorderis includes prophylaxis of gonococcal and chlamydial ophthalmia,neonatal conjunctivitis, periodontal disease, postoperativetetracycline, prophylaxis in pregnancy termination, for prevention ofskin rash/acneiform skin eruption during cancer therapy, intraoperativetopical tetracycline sclerotherapy following mastectomy for preventionof postoperative mastectomy seromas etc.

By selecting a suitable active agent, or a combination of at least twoactive agents, the foamable composition of the present disclosure isuseful in treating an animal or a human patient having any one of avariety of dermatological diseases or disorders; in alleviating suchdiseases or disorders; or where such agent or agents have shownproficiency in preventative therapy in preventing such diseases ordisorders, including but not limited to abscess, acne, acne conglobata,acne fulminans, acne vulgaris, acne scars, acute febrile neutrophilicdermatosis, acute lymphangitis, allergic contact dermatitis, alopecia,athlete's foot, atopic dermatitis, bacterial skin infections, baldness,basal cell carcinoma, blisters, bromhidrosis, bullous pemphigoid, burn,calluses candidiasis, carbuncles, cellulitis, chemical burns, chickenpox, cholesteatoma, cholinergic urticaria, chronic effects of sunlight,cold sores, cold urticaria, comedones, corns, creeping eruption,cutaneous abscess, cutaneous larva migrans, cutaneous myiasis, darkspots, delusional parasitosis, Dercum disease, dermatitis, dermatitisherpetiformis, dermatological pain, dermatological inflammation,dermographism, dermatophytoses, drug eruptions and reactions,dyshidrotic eczema, ectodermal dysplasia, eczema, eethyma, epidermoidcyst, epidermal necrolysis, erysipelas, erysipelas, erythrasma,exfoliative dermatitis, erythema multiforme, erythema nodosum,folliculitis, fungal nail infections, fungal skin infections, furuncles,gangrene, genital herpes, granuloma annulare, head lice, hidradenitissuppurativa, hives, folliculitis, hirsutism, hyperhidrosis,hypohidrosis, ichthyosis, impetigo, inflammatory acne, ingrown nails,intertrigo, irritant contact dermatitis, ischemic necrosis, itching,jock itch, Kaposi's sarcoma, keratosis pilaris, lichen simplexchronicus, lichen planus, lichen sclerosus, lymphadenitis,lymphadenitis, lymphangitis, malignant melanoma, mastocytosis, measles,melanoma, melanoma, miliaria, moles, molluscum contagiosum, MRSA,necrotizing subcutaneous infection, necrotizing fasciitis, necrotizingmyositis, nodular papulopustular acne, non-inflammatory acne, nummulardermatitis, oral herpes, panniculitis, parapsoriasis paronychia,parasitic skin infections, pemphigus, photo-allergy, photo-damage,photo-irritation, photosensitivity, papules, pediculosis, perioraldermatitis, pimples, pityriasis rosea, pityriasis Lichenoides,pityriasis rosea, pityriasis rubra pilaris, poison ivy, poison oakpost-operative or post-surgical skin conditions, pressure ulcers,pressure urticaria, pruritis, pseudofolliculitis barbae, psoriasis,PUPPP, purpura, pustules, pyogenic granuloma, rash, ringworm, rosacea,roseola, rubella, scabies, scalded skin syndrome, scarring, scleroderma,sebaceous cyst, seborrheic dermatitis, seborrheic keratosis, shingles,skin aging, skin cancer, skin neoplasia, skin neoplasms, skin rash, skinulcers, squamous cell carcinoma, staphylococcal scalded skin syndrome,stasis dermatitis, Stevens-Johnson syndrome, sunburn, sun spots, thermalburns, tinea corporis, tinea cruris, tinea pedis, tinea versicolor,toxic epidermal necrolysis, trauma or injury to the skin, varicellazoster virus, vitamin D deficiency, viral skin infections, vitiligo,warts, water hives, wrinkles, xerosis, yeast skin infections and zoster.

Likewise, the foamable composition of the present disclosure is suitablefor preventing or treating or alleviating a disorder of a body cavity ormucosal surface, e.g., the mucosa of the nose, mouth, eye, ear,respiratory system, vagina, urethra, or rectum. Non limiting examples ofsuch conditions include chlamydia infection, gonorrhea infection,hepatitis B, herpes, HIV/AIDS, human papillomavirus (HPV), genitalwarts, bacterial vaginosis, candidiasis, chancroid, granuloma Inguinale,lymphogranloma venereum, mucopurulent cervicitis (MPC), molluscumcontagiosum, nongonococcal urethritis (NGU), trichomoniasis, vulvardisorders, vulvodynia, vulvar pain, yeast infection, vulvar dystrophy,vulvar intraepithelial neoplasia (VIN), contact dermatitis, pelvicinflammation, endometritis, salpingitis, oophoritis, genital cancer,cancer of the cervix, cancer of the vulva, cancer of the vagina, vaginaldryness, dyspareunia, anal and rectal disease, anal abscess/fistula,anal cancer, anal fissure, anal warts, Crohn's disease, hemorrhoids,anal itch, pruritus ani, fecal incontinence, constipation, polyps of thecolon and rectum.

In an embodiment of the present disclosure, the composition is usefulfor the treatment of an infection. In one or more embodiments, thecomposition is suitable for the treatment of an infection, selected fromthe group of a bacterial infection, a fungal infection, a yeastinfection, a viral infection and a parasitic infection.

In an embodiment of the present disclosure, the composition is usefulfor the treatment of wound, ulcer and burn. This use is particularlyimportant since the composition of the present disclosure creates athin, semi-occlusive layer, which coats the damaged tissue, whileallowing exudates to be released from the tissue.

The composition of the present disclosure is also suitable foradministering a hormone to the skin or to a mucosal membrane or to abody cavity, in order to deliver the hormone into the tissue of thetarget organ, in any disorder that responds to treatment with a hormone.

In one embodiment the disorder is an inflammation, skin inflammation,acne, rosacea, actinic keratosis, skin cancer, a local pain, joint painand ostheoarthritis; the active agent is a nonsteroidalanti-inflammatory drug, given at a therapeutically effectiveconcentration.

In light of the hygroscopic nature of the composition, it is furthersuitable for the treatment and prevention of post-surgical adhesions.Adhesions are scars that form abnormal connections between tissuesurfaces. Post-surgical adhesion formation is a natural consequence ofsurgery, resulting when tissue repairs itself following incision,cauterization, suturing, or other means of trauma. When comprisingappropriate protective agents, the foam is suitable for the treatment orprevention of post surgical adhesions. The use of foam is particularlyadvantageous because foam can expand in the body cavity and penetrateinto hidden areas that cannot be reached by any other alternative meansof administration.

Cosmetic Use

In one or more embodiments, the composition may be used for cosmeticuse. For example it may be used as part of a cosmetic formulation toprevent a cosmetic disorder or to improve the skin. Alternatively it maybe used with cosmetic effect for example as a cosmetic remover. It canbe dispensed in small quantities as a foam targeted to a surface andapplied locally with mechanical force causing the foam to break.

Route of Administration

The formulations disclosed herein can be applied to the target site as afoam. In one or more alternative embodiments the formulations areprepared without propellant and are applied as a gel or ointment, forexample, with the tetracycline as a suspension. Application can behourly, 2 hourly, 3 hourly, four hourly, six hourly or eight hourly,twelve hourly, daily, alternate-day or intermittent, as necessary. Forreasons of compliance less frequent applications, where possible arepreferable such as twice-daily or daily single applications. In caseswhere prolonged or long term treatment is required a higher initial doseis provided followed by a gradual reduction to a lower maintenance dose,which can be increased if further outbreaks occur.

The formulations are suitable for administration directly or indirectlyto an inflicted area, in need of treatment, through the following routesof administration:

-   -   1. Topical administration: for local effect, it is applied        directly where its action is desired;    -   2. Enteral: when the desired effect is systemic (non-local), it        is given via the digestive tract; and    -   3. Parenteral: when the desired effect is systemic, it is given        by other routes than the digestive tract The following list more        specifically exemplifies some routes of administration.        1. Topical

Topical administration is any form of administration that reaches a bodyorgan topically, such as epicutaneous administration (application ontothe skin), inhalation, enema, eye drops (onto the conjunctiva), eardrops, intranasal (into the nose) and vaginal.

Exemplary dosage forms that are suitable for topical administration ofthe stable tetracycline formulations include cream, gel, liniment,lotion, ointment, paste, spray, foam, mousse, lacquer (e.g., for nailtreatment) and transdermal patch. Additionally, topical vaginal dosageforms may include a douche, an intrauterine device, a pessary (vaginalsuppository), a vaginal ring and a vaginal tablet. Rectal dosage formsinclude enema and suppositories. Inhaled dosage forms include aerosolinhalers, metered dose inhalers and solutions for nebulizer. Ophthalmicdosage forms include eye drop (solution or suspension), ophthalmic geland ophthalmic ointment. In a preferred embodiment the dosage form is afoam that is thermally stable and breakable under shear force but is not“quick breaking” which allows comfortable application and well directedadministration to the target area.

2. Enteral

Enteral is any form of administration that involves any part of thegastrointestinal tract by mouth (orally), as buccal or sublingualtablets, capsules, suspensions, solutions, powder or drops; by gastricfeeding tube, duodenal feeding tube, or gastrostomy; and rectally, insuppository or enema form.

3. Parenteral by Injection or Infusion

Intravenous (into a vein); intraarterial (into an artery); intramuscular(into a muscle); intracardiac (into the heart); subcutaneous (under theskin); intraosseous infusion (into the bone marrow); intradermal, (intothe skin itself); intrathecal (into the spinal canal); andintraperitoneal (into the peritoneum).

4. Other Parenteral

Transdermal (diffusion through the intact skin); transmucosal (diffusionthrough a mucous membrane), e.g. insufflation (snorting), sublingual,buccal (absorbed through cheek near gumline) and vaginal; andinhalational; epidural (synonym: peridural) (injection or infusion intothe epidural space); and intravitreal.

EXAMPLES

The invention is described with reference to the following examples, ina non-limiting manner. The following examples exemplify the compositionsand methods described herein. The examples are for the purposes ofillustration only and are not intended to be limiting. Many variationswill suggest themselves and are within the full intended scope.

Example 1 General Manufacturing Procedures

The following procedures are used to produce foam samples described inthe examples below, in which only the steps relevant to each formulationare performed depending on the type and nature of ingredients used.

Step 1: Hydrophobic solvents are heated to 60-70° C.

Step 2: Waxes (and any fatty alcohols, if at all present, fatty acids,if at all present, or surfactants, if at all present) are added to thehydrophobic solvent and the formulation is mixed until complete melting.

Step 3: The formulation is cooled down to 30-40° C., active ingredients,if present, are added and the formulation is mixed until homogeneity isobtained.

Step 4: The formulation is cooled down to room temperature under mixingand packaged into suitable containers.

Materials

TABLE 1 Exemplary possible ingredients suitable for the production offoamable compositions disclosed herein. Equivalent materials from othermanufacturers can also be used satisfactorily. Chemical Name FunctionCommercial Name Supplier Beeswax white Foam adjuvant Beeswax white HenryLamotte Benzoyl Peroxide Active agent Benzoyl Peroxide Spectrum C12-15Alkyl Benzoate Solvent C12-15 Alkyl Benzoate Degussa Calcitriol Activeagent Calcitriol Solvay Pharmaceutical Capric/caprylic triglyceridesSolvent Captex 355 Abitec Cyclomethicone-5 Solvent ST-cyclomethicone-5Dow Heavy Mineral Oil Solvent Paraffin oil liquid heavy GadotHydrogenated castor oil Foam adjuvant Cutina HR Cognis Isopropylmyristate Solvent Isopropyl Myristate Ph. Cognis Isopropyl palmitateSolvent Isopropyl Palmitate Cognis Lidocaine Active agent LidocaineSigma Light Mineral Oil Solvent Pioner 2076P Hansen & RosenthalMinocycline HCl Active agent Minocycline HCl Hovione Mometasone FuroateActive agent Mometasone Furoate Sicor de Mexico Octyldodecanol SolventEutanol G Cognis Paraffin wax 42-44 Wax Paraffin 42-44 Merck Paraffinwax 51-53 Wax Paraffin 51-53 Merck Paraffin wax 58-62 Wax Paraffin 58-62Merck PPG 15 stearyl ether Solvent Arlamol E UniqemaPropane/Isobutane/Butane (20:78:2) Propellant A-46 AeropresPropane/Isobutane/Butane (55:18:27) Propellant AP-70 AeropresTetrafluoroethane Propellant Dymel 134a DuPont

By way of non-limiting example, tests are briefly set out below as wouldbe appreciated by a person of the art.

Collapse Time, which is a measure or indication of thermal stability, isexamined by dispensing a given quantity of foam and photographingsequentially its appearance with time during incubation at 36° C. Thecollapse time result is defined as the time when the foam height reaches50% of its initial height or if the foam has not yet reached 50% of itsinitial height after say 180 seconds then the collapse time is recordedas being >180 seconds. By way of illustration one foam may remain at100% of its initial height for three minutes, a second foam may reach90% of its initial height after three minutes, a third foam may reach70% of its initial height after three minutes, and a fourth foam mayreach 51% of its initial height after three minutes, nevertheless ineach of these four cases the collapse time is recorded as >180 secssince for practical purposes for easy application by a patient to atarget the majority of the foam remains intact for more than 180 secs.If the foam for example reaches 50% of its original height after say 100seconds it would be recorded as having a collapse time of 100 seconds.It is useful for evaluating foam products, which maintain structuralstability at skin temperature for at least 1 minute. Foams which arestructurally stable on the skin for at least one minute are termed“short term stable” carriers or foams. A rough corollary of collapsetime is drainage. If the collapse time is short the drainage is high.Each bubble is comprised of a liquid phase surrounding an air or gasphase. The liquid drains under the influence of gravitation force. Whena bubble thins it ultimately collapses or joins with anther bubble. Sofoams with high drainage are inherently unstable. A further factor isexpansion time. Some foams expand very rapidly whilst others expandquite slowly. Expansion time is a measure of how long a foam may take toreach its full expansion or lowest density. In some cases expansion andcollapse can offset one another to some degree. So in one aspect, forexample, whilst a foam is still expanding it has also begun to collapse.In another aspect, a thermolabile formulation that can collapse quitequickly in seconds upon expose to body temperature of about 36° C. maynevertheless have quite a relatively long expansion time at 20° C. Incertain aspects the collapse time, expansion time and drainage time canall be long.

Density: in this procedure, the foam product is dispensed into vessels(including dishes or tubes) of a known volume and weight. Replicatemeasurements of the mass of foam filling the vessels are made and thedensity is calculated. The canister and contents are allowed to reachroom temperature. Shake the canister to mix the contents and dispenseand discard 5-10 mL. Then dispense foam into a pre-weighed tube, fillingit until excess is extruded. Immediately remove (level off) excess foamat both ends and weigh the filled tube on the weighing balance.

Viscosity is measured with Brookfield LVDV-II+PRO with spindle SC4-25 atambient temperature and 20, 10, 5 and or 1 RPM. Viscosity is usuallymeasured at 10 RPM or 20 RPM. However, at about the apparent upper limitfor the spindle of ˜>50,000 CP, the viscosity at 1 RPM may be measured,although the figures are of a higher magnitude.

Shakability represents the degree to which the user is able to feel/hearthe presence of the liquid contents when the filled pressurized canisteris shaken. Shaking is with normal mild force without vigorous shaking orexcessive force. When the user cannot sense the motion of the contentsduring shaking the product may be considered to be non-shakable. Thisproperty may be of particular importance in cases where shaking isrequired for affecting proper dispersion of the contents.

Table of Shakability scoring Good shakability (conforms to requiredquality specification) 2 Moderate shakability (conforms to requiredquality specification) 1 Not shakable (fails to meet required qualityspecification) but may 0 still be flowable and allow foam formation ofquality Is substantially not able to pass through valve Block

Bubble Size: Foams are made of gas bubbles entrapped in liquid. Thebubble size and distribution reflects in the visual texture andsmoothness of the foam. Foam bubbles size is determined by dispensing afoam sample on a glass slide, taking a picture of the foam surface witha digital camera equipped with a macro lens. The diameter of about 30bubbles is measured manually relatively to calibration standardtemplate. Statistical parameters such as mean bubble diameter, standarddeviation and quartiles are then determined. Measuring diameter may alsobe undertaken with image analysis software. The camera is a Nikon D40XCamera (resolution 10 MP) equipped with Sigma Macro Lens (ref: APO MACRO150 mm F2.8 EX DG HSM). Pictures obtained are cropped to keep a squaredregion of 400 pixels×400 pixels.

Chemical Stability: the amount of active agent present is analyzedchromatographically. Analysis is carried out after formulationpreparation and at appropriate time intervals thereafter. The samplesare typically stored in controlled temperature incubators at one or moreof 5° C., 25° C. and 40° C. for several weeks or months. At appropriatetime intervals samples are removed from the incubators and theconcentration of active agent and or breakdown product is measured.

Example 2 Formulations Containing Waxes and Propellant or Oil andPropellant

The foaming properties of formulations containing waxes and propellantwith no additional solvent were studied. Formulations were preparedcontaining Paraffin wax 51-53 and different concentrations ofpropellant. Also a formulation with mineral oil and propellant wasprepared. As shown in Tables 2a and 2b below, upon addition ofpropellant, the formulations did not produce foam. It can be appreciatedthat the formulation of quality waterless foams based on waxes ischallenging without the presence of foam stabilizers such as surfactantseither alone or combined with foam adjuvants.

TABLE 2a Formulations containing waxes and propellant Formulations 001002 003 % w/w % w/w % w/w Ingredients Paraffin wax 51-53 100.0 100.0100.0 Total 100.0 100.0 100.0 Propellant AP-70 30.0 50.0 60.0 ResultsFoam Quality No Foam No Foam No Foam

TABLE 2b Formulation containing oil and propellant Formulations XX2b %w/w Ingredients Light mineral oil 100.0 Total 100.0 Propellant AP-7010.0 Results Foam Quality PoorComment: Neither Mineral Nor Paraffin Waxes Alone were Able to Generatea Foam.

Example 3 Mineral Oil-Based Formulations Containing Waxes

The foaming properties of mixtures of oils and waxes were studied.Formulations were prepared containing oils such as mineral oils andsilicones in combination with waxes such as Paraffin wax 42-44, beeswaxand hydrogenated castor oil were prepared, where the concentration ofwax was from 10% to 20%. As shown in Table 3 below, upon addition ofpropellant, formulations 1-4 produced no more than bubbly liquids andformulations 8-10, although they were better, still only producedunstable fairly good quality foams that collapsed within seconds. It canbe appreciated that the formulation of stable quality foams based on acombination of oils and waxes is challenging without the presence offoam stabilizers such as surfactants either alone or combined with foamadjuvants. Of all the formulations, parafin wax and mineral oil achievedthe poorest result. Without being bound by any theory the variationsbetween paraffin waxes and their success in generating foams may be dueto one or more factors such as chain length, van der Waals forces, andCST as explained above in the discussion.

TABLE 3 Mineral oil-based formulations containing waxes Formulations 004005 006 007 008 009 010 Ingredients % w/w % w/w % w/w % w/w % w/w % w/w% w/w Heavy mineral oil 80.0 60.0 80.0 60.0 60.0 85.0 85.0 Light Mineraloil — 30.0 — 25.0 25.0 — — Cyclomethicone — — — 5.00 5.00 — — Paraffinwax 42-44 20.0 — — — — — — Beeswax — 10.0 20.0 5.0 — — — Hydrogenatedcastor oil — — — 5.0 10.0 15.0 15.0 Total 100.0 100.0 100.0 100.0 100.0100.0 100.0 Propellant AP-70 8.0 — 8.0 — — 8.0 12.0 Propellant A-46 —12.0 — 12.0 12.0 — — Results Foam Quality Poor Fair Fair Fair FairlyFairly Fairly Good Good Good Collapse Time at 36° C. (sec) — — — — 10 ——

Example 4 Mineral Oil-Based Foam Formulations Containing 51-53 or 42-44Paraffin Waxes

The foaming properties of formulations containing mineral oil and aparaffin wax having a melting point of about 51-53° C. were studied. Asshown in Table 4a, 4b and 4c below, formulations containing 5% pararafinwax 51-53° C. (and by extrapolation less than 5%) only produced bubblyliquids. 7.5% paraffin wax 51-53° C. only produced fairly good foam.Formulations containing 55% and 60% pararafin wax 51-53° C. (and byextrapolation more than 60%) did not produce foam and a semi-solidcontent was expelled even upon increasing the concentration ofpropellant to 12% and to 16%. However, formulations containing from 10%to 50% paraffin wax 51-53, successfully generated good to excellentquality foams having a collapse time of about 2 minutes or higher at 36°C. These results are surprising given the fact that no known foamstabilizing agent such as surfactants is present and that the phenomenais concentration dependent. Moreover, no foam adjuvant such as a fattyalcohol or fatty acid is needed, and formulations containing only waxesgenerated quality foams. For high amounts of waxes, the inclusion ofhigher amounts of propellant was found useful, for example, in order toimprove the flowability of the formulation within the canister, as canbe shown in by the shakability results. For example, a formulationcontaining 50% heavy mineral oil and 50% paraffin wax 51-53 waspressurized with 8% propellant or 12% propellant (See Table 4c). With 8%propellant, the composition was such that a block occurred withsubstantially no content being expelled through the canister valve.However, increasing the amount of propellant to 12% enabled quality foamto be expelled. Additionally, as can be seen from formulations 31-34that increasing propellant from 8% to 12% also resulted in a similarincrease in collapse time from about 80 secs to about 120 secs. Withoutbeing bound by any theory it may be that the propellant was successfulin reducing the viscosity of the formulation and or wax in the valve.The physical properties of formulation 016 containing 20% paraffin wax51-53 are presented in Table 4e.

Formulations were prepared, based on the combination of mineral oil witha paraffin wax having a melting point of about 42-44° C. Both in thecase of light and heavy mineral oil, breakable foams of quality wereobtained having a collapse time of more than 1 minute at 36° C. when 40%of paraffin wax 42-44 was used. Notably, the stability of the foams at36° C. was improved by using higher amounts of propellant.

Formulations were prepared, based on the combination of mineral oil witha paraffin wax having a melting point of about 58-62° C. Breakable foamsof quality having a density between 0.1 and 0.2 g/mL and a collapse timeof more than 3 minute at 36° C. were obtained when 10% and 20% ofparaffin wax 58-62 were used.

Table 4e indicates that the formulation can exist as three separatephases when left to stand, viz, oil, wax, and propellant butre-disperses on moderate shaking

In one or more embodiments, there is provided a foamable formulationcontaining a mineral oil, a paraffin wax and a propellant, wherein theformulation provides upon dispensing a breakable foam of quality whichexhibits a collapse time when placed on a surface at 36° C. (or betweenabout 20° C. to 36° C.) of about or more than 1 minute. In one or moreembodiments the collapse time is about or more than 1½ minutes; is aboutor more than 2 minutes; is about or more than 2½ minutes; or is about ormore than 3 minutes.

TABLE 4a Mineral oil-based foam formulations containing paraffin waxesFormulations 011 012 013 014 015 016 017 018 Ingredients % w/w % w/w %w/w % w/w % w/w % w/w % w/w % w/w Heavy mineral oil 95.0 92.5 90.0 87.585.0 80.0 75.0 72.5 Paraffin wax 51-53 5.0 7.5 10.0 12.5 15.0 20.0 25.027.5 Total 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 PropellantAP-70 8.0 8.0 8.0 8.0 8.0 8.0 8.0 8.0 Results Foam Quality Poor FairlyGood- Good Excellent Excellent Excellent Excellent Good Shakability 2 22 2 2 2 1 1 Collapse Time at 36° C. (sec) — — 110 135 >180 >180 >180>180

TABLE 4b Mineral oil-based foam formulations containing paraffin waxes(cont.) Formulations 019 020 021 022 023 024 025 026 Ingredients % w/w %w/w % w/w % w/w % w/w % w/w % w/w % w/w Heavy mineral oil 70 67.5 65.065.0 60.0 60.0 55.0 55.0 Paraffin wax 51-53 30 32.5 35.0 35.0 40.0 40.045.0 45.0 Total 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0Propellant AP-70 8.0 8.0 8.0 12.0 8.0 12.0 8.0 12.0 Results Foam QualityExcellent Excellent Excellent Excellent Excellent Excellent BlockExcellent Shakability 1 1 1 2 0 1 — 0 Collapse Time at 36° C.(sec) >180 >180 >180 >180 >180 >180 — >180

TABLE 4c Mineral oil-based foam formulations containing paraffin waxes(cont.) Formulations 027 028 XX4ca XX4cb 029 030 031 032 033 034Ingredients % w/w % w/w % w/w % w/w % w/w % w/w % w/w % w/w % w/w % w/wHeavy mineral oil 50.0 50.0 35.0 30.0 — — 60.0 60.0 — — Light Mineraloil — — — — 60.0 60.0 — — 60.0 60.0 Paraffin wax 42-44 — — — — — — 40.040.0 40.0 40.0 Paraffin wax 51-53 50.0 50.0 55.0 60.0 40.0 40.0 — — — —Total 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0Propellant AP-70 8.0 12.0 8 or 12 16.0 8.0 12.0 8.0 12.0 8.0 12.0 or16.0 Results Foam Quality Block Excellent No foam No foam ExcellentExcellent Excellent Excellent Excellent Excellent (semi- (semi- solidsolid content content expelled) expelled) Shakability — 0 1 1 1 2 1 2 12 Collapse Time at — >180 — — >180 >180 85 120 80 125 36° C. (sec)

TABLE 4d Mineral oil-based foam formulations containing paraffin waxes(cont.) Formulations 035 036 037 038 % w/w % w/w % w/w % w/w IngredientsHeavy mineral oil 90.0 80.0 80.0 70.0 C12-C15 Alkyl benzoate — — — 10.0Paraffin wax 58-62 10.0 20.0 20.0 20.0 Total Propellant AP-70 8.0 8.012.0 12.0 Results Foam Quality Excellent Excellent Excellent ExcellentFoam Density (g/ml) 0.135 0.119 0.129 0.177 Shakability 1 1 2 2 CollapseTime at 36° C. >180 >180 >180 >180 (sec)

TABLE 4e Physical properties of formulation 016 Formulations 016 % w/wIngredients Heavy mineral oil 80.0 Paraffin wax 51-53 20.0 TotalPropellant AP-70 8.0 Results Foam Quality E Shakability 2 Density (g/ml)0.230 Collapse Time at 36° C. (sec) >180 Expansion time (sec) 240Hardness (g) 9 Total dispensed weight (%) 82.40 Mean Bubble size (nm)259 Inspection in Pressurized Glass bottle 3 phases PFF Centrifugation3K rpm for 10 min 3 phases PFF Centrifugation 10K rpm for 10 min 3phases PFF Viscosity at 10 rpm (cP) 4303

The following example illustrates the physical stability of oleaginousfoam formulation 016. In an accelerated stability study, samples werestored at 40° C., and parameters indicating physical stability such asfoam quality, shakability, foam density and foam collapse time weredetermined. The stability test results following 1 and 2 months ofstorage at 40° C. are shown in Table 4f.

TABLE 4F Physical properties of formulation 016 after 1 and 2 months at40° C. 2 months Tests T0 1 month at 40° C. at 40° C. Foam Quality E E EShakability Good Poor - after vigorous Poor - after vigorous shakingbecame shaking moderate good Foam Density 0.225 0.221 0.235 (g/ml)Collapse Time >180 >180 >180 at 36° C. (sec)

Formulation 016 is physically stable after 2 months of storage at 40° C.The decrease in formulation shakability may be explained by a partialsolidification of the wax content with time. It may be overcome interalia by increasing the propellant concentration of the formulation toabout 12%, or by using a propellant having a higher vapor pressure suchas propane. So for example a smaller amount of higher pressurepropellant may be used instead of a higher amount of a lower pressurepropellant. In one or more embodiments the amount of propellant is atleast about 11%; is at least about 12%; is at least about 13%; is atleast about 14%; is at least about 15%; is at least about 16%; is atleast about 17%; or is at least about 18%. In one or more embodimentsthe vapor pressure of the propellant is at least about 10 psi; is atleast about 30 psi; is at least about 50 psi; is at least about 70 psi;is at least about 90 psi; is at least about 110 psi; is at least about130 psi; or is at least about 150 psi. In one or more embodiments thevapor pressure of the propellant is between about 25 psi to about 125psi. In one or more embodiments the vapor pressure of the propellant isbetween about 10 psi to about 130 psi. In one or more embodiments thevapor pressure of the propellant is between about 10 psi to about 30psi; between about 25 psi to about 50 psi; between about 50 psi to about70 psi; between about 70 psi to about 30 psi; between about 70 psi toabout 90 psi; between about 90 psi to about 130 psi; between about 110psi to about 130 psi; between about 30 psi to about 110 psi; betweenabout 40 psi to about 90 psi.

Example 5 Foam Formulations Containing Waxes and Various Oils

The foaming properties of formulations containing various hydrophobicsolvents and a paraffin wax having a melting point of about 51-53° C.were studied. As shown in Table 5 below, formulations containing oilsuch as capric/caprylic triglycerides, PPG-15 Stearyl ether, isopropylpalmitate, isopropyl myristate or octyldodecanol combined with 20%paraffin wax 51-53 produced breakable foams of quality having a collapsetime of more than 1 minute at 36° C.

In one or more embodiments, there is provided a foamable formulationcontaining a hydrophobic solvent, a paraffin wax and a propellant,wherein the formulation provides upon dispensing a breakable foam ofquality which exhibits a collapse time when placed on a surface at 36°C. (or between about 20° C. to 36° C.) of about or more than 1 minute.In one or more embodiments the collapse time is about or more than 1½minutes; is about or more than 2 minutes; is about or more than 2½minutes; is about or more than 3 minutes

TABLE 5 Foam formulations containing waxes and various oils Formulations039 040 041 042 043 % w/w % w/w % w/w % w/w % w/w IngredientsCapric/caprylic 80.0 — — — — triglycerides PPG-15 Stearyl — 80.0 — — —ether Isopropyl palmitate — — 80.0 — — Isopropyl myristate — — — 80.0 —Octyldodecanol — — — — 80.0 Paraffin wax 51-53 20.0 20.0 20.0 20.0 20.0Total 100.0 100.0 100.0 100.0 100.0 Propellant AP-70 8.0 8.0 8.0 8.0 8.0Results Foam Quality Excellent Excellent Good Good Good Shakability 2 22 2 2 Collapse Time at >180 >180 180 >180 165 36° C. (sec)

Example 6 Foam Formulations Containing Oils, Waxes and VariousPropellants

The foaming properties of formulations containing mineral oil, aparaffin wax and various types of propellants were studied. As shown inTable 6 below, formulations containing hydrocarbon propellants such asAP-70 and A-46, and hydrofluorocarbon propellants such as Dymel 134aproduced breakable foams of quality having a collapse time of more than1 minute at 36° C.

TABLE 6 Foam formulations containing oils, waxes and various propellantsFormulations 044 045 046 % w/w % w/w % w/w Ingredients Heavy mineral oil80.0 80.0 80.0 Paraffin wax 51-53 20.0 20.0 20.0 Total 100.0 100.0 100.0Propellant AP-70 (vapor pressure = 8.0 — — 70 psi) Propellant A-46(vaporpressure = — 8.0 — 46 psi) Propellant Dymel 134a (vapor — — 15.0pressure = 96.6 psi) Results Foam Quality Excellent Good ExcellentShakability 2 2 2 Collapse Time at 36° C. (sec) >180 >180 >180

Example 7 Foam Formulations Containing Oils, and Various Waxes

The foaming properties of formulations containing mineral oil, apropellant and other types of waxes were studied. As shown in Table 7below, formulations containing solid waxes, namely about 20%hydrogenated castor oil, and formulations containing about 30% or about40% beeswax produced breakable foams of quality having a collapse timeof more than 1 minute at 36° C. For high amounts of waxes, the inclusionof higher amounts of propellant was found useful in order to improve theflowability of the formulation within the canister, as can be shown inby the shakability results.

In one or more embodiments, there is provided a foamable formulationcontaining a hydrophobic solvent, a wax and a propellant, wherein theformulation provides upon dispensing a breakable foam of quality whichdoes not collapse at 36° C. for more than 1 minute.

TABLE 7 Foam formulations containing oils, waxes and other waxesFormulations 047 048 049 050 051 052 Ingredients % w/w % w/w % w/w % w/w% w/w % w/w Heavy mineral oil 80.0 80.0 60.0 60.0 70.0 70.0 Beeswax — —40.0 40.0 30.0 30.0 Hydrogenated castor oil 20.0 20.0 — — — — Total100.0 100.0 100.0 100.0 100.0 100.0 Propellant AP-70 8.0 12.0 8.0 12.08.0 12.0 Results Foam Quality Good Good Good Excellent Good GoodShakability 0 0 0 1 1 2 Collapse Time at 36° C. (sec) — >180 — >180 >180>180

Example 8 Foam Formulations Containing Oils, Waxes and Various ActiveIngredients

The foaming properties of formulations containing mineral oil, aparaffin wax, a propellant and various active ingredients were studied.As shown in Table 8 below, formulations containing minocycline HCl,benzoyl peroxide (BPO), mometasone fuorate, calcitriol and lidocaineproduced breakable foams of quality having a collapse time of more than1 minute at 36° C. However, BPO and paraffin wax formed a block onrepeated use.

TABLE 8 Foam formulations containing oils, waxes and various activeingredients Formulations 053 054 055 056 057 % w/w % w/w % w/w % w/w %w/w Ingredients Heavy mineral oil 79.0 75.0 79.9 79.9985 75.0 Paraffin51-53 20.0 20.0 20.0 20.0 20.0 Minocycline HCL 1.0 — — — — Benzoylperoxide — 5.0 — — — Mometasone furoate — — 0.10 — — Calcitriol — — —0.0015 — Lidocaine — — — — 5.0 Total 100.0 100.0 100.0 100.0 100.0Propellant AP-70 8.0 12.0 8.0 12.0 8.0 Results Foam Quality ExcellentExcellent Excellent Excellent Excellent Shakability 2 2 2 2 2 CollapseTime at 36° C. (sec) >180 Block >180 >180 >180

Example 9 Compatibility Study

Procedure: Minocycline hydrochloride (“MCH”) was incubated as asuspension with various excipients at 25° C. and 40° C. for maximum ofsixty days or to the point where degradation was suspected. The ratiobetween MCH and the tested excipient is detailed below. Visualinspection was the major criterion for indication of compatibility. Thecolor of intact MCH suspension is pale yellow; and any change of color(e.g., to dark orange, red, green, brown and black) indicates oxidationor degradation.

Hydrophilic solvents were tested for compatibility with MCH at a ratioof MCH:excipient of 1:250. Dimethyl Isosorbide, Glycerin, Ethanol,Propylene glycol, Butylene Glycol, PEG 200, Hexylene Glycol, PEG 400,Dimethyl Sulfoxide and Diethylene glycol monoethyl ether were found tobe incompatible with MCH.

Oily emollients and waxes were tested for compatibility with MCH at aratio of MCH:excipient of 1:250 for Oily emollients and 1:50 for waxes.Hydrogenated castor oil, Castor oil, Cocoglycerides, Disopropyl adipate,Mineral oil light, Coconut oil, Beeswax, MCT oil, Cyclomethicone,Isododecane, Cetearyl octanoate, Gelled mineral oil, Isopropylmyristate, PPG 15 stearyl ether, Mineral oil heavy, Octyl dodecanol,White Petrolatum, Petrolatum (Sofinetic), Paraffin 51-53, Calendula oil,Shea butter, Grape seed oil, Almond oil, Jojoba oil, Avocado oil, Peanutoil, Wheat germ oil and Hard Fat were found to be compatible with MCH.Pomegranate seed oil was found to be incompatible with MCH.

The compatibility of MCH with hydrophobic surfactant was testedfollowing solubilization of the surfactant in mineral oil (mineral oilwas previously shown to be compatible with MCH). Surfactants were testedfor compatibility with MCH at a ratio of MCH:excipient of 1:50. PEG150distearate, Laureth 4, PEG 40 hydrogenated castor oil, PEG 75 lanolin,Glucam P20 distearate, PEG100 stearate, Glyceryl monostearate, PEG 40stearate, Montanov S (Cocoyl Alcohol (and) C12-20 Alkyl Glucoside)),Alkyl lactate, Benton gel, SPAN 60, Sorbitan sesquistearate, SPAN 40,Tween 20, Ceteth 2, Sucrose stearic acid esters D1813, Ceteareth 20,Steareth 2/Steareth 21, Methyl glucose sesquistearate, Oleth 20, PPG 20methyl glucose ether, Tween 60 were found to be incompatible with MCH.Sucrose stearic acid esters D1803, Sucrose stearic acid esters D1807 andSucrose stearic acid esters D1811 were found to be compatible with MCH;however, not all of them dissolved in oil (e.g. 1811, 1813).

Foam adjuvants were tested for compatibility with MCH at a ratio ofMCH:excipient of 1:50. Isostearyl alcohol, Behenyl alcohol, Stearylalcohol, Cetyl alcohol, Oleyl alcohol, Myristyl alcohol, Cetostearylalcohol, Palmitic acid, Stearic acid and Oleic acid were found to becompatible with MCH. Isostearic acid was not compatible with MCH.

Additives were tested for compatibility with MCH at a ratio ofMCH:excipient of 1:50. Aerosil and Menthol were found to be compatiblewith MCH. Titanium dioxide and Ethocel were not compatible with MCH.

Additives were tested for compatibility with MCH. Minimal quantities ofwater (1004) were added to MCH, suspended in excipients that haddemonstrated compatibility to examine whether water can enhanceoxidation/degradation in the absence or presence of antioxidant. Inparallel, antioxidants were added to the MCH suspensions comprisingwater. Antioxidants were also added to excipients which were found to benon compatible with MCH. Addition of water caused prompt degradation ofMCH. Addition of the antioxidants alpha-tocopherol, BHA/BHT and propylgallate did not prevent MCH degradation. Compatible excipients becameincompatible in the presence of water. Addition of antioxidants did notalter this result.

The invention claimed is:
 1. A waterless foamable composition free ofsurfactant and polymeric agent comprising: a carrier comprising: a)about 50% to about 90% by weight of the carrier of a liquid oil andabout 10% to about 50% by weight of the carrier of a paraffin wax thathas a melting point between about 47° C. and about 64° C., wherein thetotal weight of the liquid oil and paraffin wax together is betweenabout 85% and about 100% by weight of the carrier; or b) about 40% byweight of the carrier of a liquid oil and about 60% by weight of thecarrier of a paraffin wax that has a melting point between about 42° C.and about 44° C.; and a liquefied or compressed gas propellant; and atetracycline antibiotic; wherein the ratio of the carrier to thepropellant is from about 100:4 to about 100:25; wherein the compositioncomprises less than 5% foam adjuvant; and wherein upon dispensing thefoamable composition from a container, the composition forms a breakablefoam that is stable, yet breaks easily upon application of shear force.2. The composition of claim 1, further comprising at least one activeagent.
 3. The composition of claim 2, wherein the active agent isselected from the group consisting of an active herbal extract, anacaricide, an age spot and keratose removing agent, an allergen, analpha hydroxyl acid, an analgesic agent, an antiacne agent, anantiallergic agent, an antiaging agent, an antibacterial agent, anantibiotic, an antiburn agent, an anticancer agent, an antidandruffagent, an antidepressant, an antidermatitis agent, an antiedemic agent,an antifungal agent, an antihistamine, an antihelminth agent, anantihyperkeratolyte agent, an anti-infective agent, an antiinflammatoryagent, an antiirritant, an antilipemic agent, an antimicrobial agent, anantimycotic agent, an antioxidant, an antiparasitic agent, anantiproliferative agent, an antipruritic agent, an antipsoriatic agent,an antirosacea agent, an antiseborrheic agent, an antiseptic agent, anantiswelling agent, an antiviral agent, an anti-wart agent, ananti-wrinkle agent, an antiyeast agent, an astringent, a beta-hydroxyacid, benzoyl peroxide, a topical cardiovascular agent, achemotherapeutic agent, a corticosteroid, an immunogenic substance, adicarboxylic acid, a disinfectant, a fungicide, a hair growth regulator,a haptene, a hormone, a hydroxy acid, an immunosuppressant, animmunoregulating agent, an immunomodulator, an insecticide, an insectrepellent, a keratolytic agent, a lactam, a local anesthetic agent, alubricating agent, a masking agent, a metals, a metal oxide, a mitocide,a neuropeptide, a non-steroidal anti-inflammatory agent, an oxidizingagent, a pediculicide, a peptide, a protein, a photodynamic therapyagent, a radical scavenger, a refatting agent, a retinoid, a sanative, ascabicide, a self tanning agent, a skin protective agent, a skinwhitening agent, a steroid, a steroid hormone, a vasoconstrictor, avasodilator, a vitamin, a vitamin A, a vitamin A derivative, a vitaminB, a vitamin B derivative, a vitamin C, a vitamin C derivative, avitamin D, a vitamin D derivative, a vitamin D analog, a vitamin F, avitamin F derivative, a vitamin K, a vitamin K derivative, a woundhealing agent and a wart remover, an androgen, an anti-hyperkeratosisagent, an estrogen, an immunestimulant, a pesticide, a progesterone, asedative, a vaso active agent, and a mixture of any two or more thereof.4. The composition of claim 1, wherein the tetracycline antibiotic is aminocycline or a doxycycline.
 5. The composition of claim 3, wherein theactive agent is a retinoid.
 6. The composition of claim 1, wherein thecarrier comprises about 1% or less than 1% by weight of a foam adjuvant.7. The composition of claim 1, wherein the composition is foam adjuvantfree.
 8. The composition of claim 1, wherein the carrier comprises about5% or less than 5% by weight of the carrier of polyols.
 9. Thecomposition of claim 1, wherein the paraffin wax is selected from thegroup consisting of a paraffin wax 58-62° C., a paraffin wax 51-53° C.,and a paraffin wax 42-44° C., and a mixture thereof.
 10. The compositionof claim 1, wherein the composition is free of short chain alcohols. 11.The composition of claim 1, wherein the composition is a single phase.12. The composition of claim 1, further comprising a solid or semi-solidoil.
 13. The composition of claim 1, wherein the composition is shortchain alcohol free and polyol free.
 14. The composition of claim 1,wherein the propellant is a hydrocarbon propellant or ahydrofluorocarbon or another environmentally acceptable propellant. 15.The composition of claim 1, wherein the composition further comprises awax selected from a hydrogenated castor oil, beeswax, and a mixturethereof.
 16. The composition of claim 2, wherein the active agent issuitable for treating a disorder selected form the group consisting ofabscess, acne, acne conglobata, acne fulminans, acne vulgaris, acnescars, acute febrile neutrophilic dermatosis, acute lymphangitis,allergic contact dermatitis, alopecia, athlete's foot, atopicdermatitis, bacterial skin infections, baldness, basal cell carcinoma,blisters, bromhidrosis, bullous pemphigoid, burn, calluses candidiasis,carbuncles, cellulitis, chemical burns, chicken pox, cholesteatoma,cholinergic urticaria, chronic effects of sunlight, cold sores, coldurticaria, comedones, corns, creeping eruption, cutaneous abscess,cutaneous larva migrans, cutaneous myiasis, dark spots, delusionalparasitosis, Dercum disease, dermatitis, dermatitis herpetiformis,dermatological pain, dermatological inflammation, dermographism,dermatophytoses, drug eruptions and reactions, dyshidrotic eczema,ectodermal dysplasia, eczema, ecthyma, epidermoid cyst, epidermalnecrolysis, erysipelas, erysipelas, erythrasma, exfoliative dermatitis,erythema multiforme, erythema nodosum, folliculitis, fungal nailinfections, fungal skin infections, furuncles, gangrene, genital herpes,granuloma annulare, head lice, hidradenitis suppurativa, hives,folliculitis, hirsutism, hyperhidrosis, hypohidrosis, ichthyosis,impetigo, inflammatory acne, ingrown nails, intertrigo, irritant contactdermatitis, ischemic necrosis, itching, jock itch, Kaposi's sarcoma,keratosis pilaris, lichen simplex chronicus, lichen planus, lichensclerosus, lymphadenitis, lymphadenitis, lymphangitis, malignantmelanoma, mastocytosis, measles, melanoma, miliaria, moles, molluscumcontagiosum, MRSA, necrotizing subcutaneous infection, necrotizingfasciitis, necrotizing myositis, nodular papulopustular acne,non-inflammatory acne, nummular dermatitis, oral herpes, panniculitis,parapsoriasis paronychia, parasitic skin infections, pemphigus,photo-allergy, photo-damage, photo-irritation, photosensitivity,papules, pediculosis, perioral dermatitis, pimples, pityriasis rosea,pityriasis Lichenoides, pityriasis rosea, pityriasis rubra pilaris,poison ivy, poison oak post-operative or post-surgical skin conditions,pressure ulcers, pressure urticaria, pruritis, pseudofolliculitisbarbae, psoriasis, PUPPP, purpura, pustules, pyogenic granuloma, rash,ringworm, rosacea, roseola, rubella, scabies, scalded skin syndrome,scarring, scleroderma, sebaceous cyst, seborrheic dermatitis, seborrheickeratosis, shingles, skin aging, skin cancer, skin neoplasia, skinneoplasms, skin rash, skin ulcers, squamous cell carcinoma,staphylococcal scalded skin syndrome, stasis dermatitis, Stevens-Johnsonsyndrome, sunburn, sun spots, thermal burns, tinea corporis, tineacruris, tinea pedis, tinea versicolor, toxic epidermal necrolysis,trauma or injury to the skin, varicella zoster virus, vitamin Ddeficiency, viral skin infections, vitiligo, warts, water hives,wrinkles, xerosis, yeast skin infections, and zoster.
 17. Thecomposition of claim 1, wherein the composition comprises less than 1%foam adjuvant.
 18. The composition of claim 1, wherein the compositionis free of foam adjuvants having a gel building role.
 19. A waterlessfoamable composition free of surfactant and polymeric agent comprising:a carrier comprising: a) about 50% to about 90% by weight of the carrierof a liquid oil and about 10% to about 50% by weight of the carrier of aparaffin wax selected from the group consisting of a paraffin wax 58-62°C., a paraffin wax 51-53° C., and a mixture thereof, wherein the totalweight of the liquid oil and wax together is between about 85% and about100% by weight of the carrier; or b) about 40% by weight of the carrierof a liquid oil and about 60% by weight of the carrier of a paraffin wax42-44° C.; and a liquefied or compressed gas propellant, wherein the gaspropellant has a vapor pressure of about 40 to about 90 psi; wherein theratio of the carrier to the propellant is from about 100:4 to about100:25; wherein the composition comprises less than 5% foam adjuvant;wherein the foamable composition is flowable; and wherein upondispensing the foamable composition from a container, the compositionforms a breakable foam that is stable, yet breaks easily uponapplication of shear force.
 20. The composition of claim 19, wherein thecomposition further comprises a tetracycline antibiotic.
 21. Thecomposition of claim 19, wherein the foamable composition comprisesabout 5% to about 16% by weight of the gas propellant.
 22. Thecomposition of claim 19, wherein the foamable composition comprisesabout 7% to about 17% of the gas propellant.
 23. The composition ofclaim 19, wherein the foamable composition comprises less than about0.1% by weight polymeric agent.
 24. A waterless foamable compositionfree of surfactant and polymeric agent comprising: a carrier comprising:a) about 60% to about 85% by weight of the carrier of a liquid oil andabout 15% to about 40% by weight of the carrier of a paraffin wax 58-62°C., a paraffin wax 51-53° C., and a mixture thereof, wherein the totalweight of the liquid oil and wax together is between about 85% and about100% by weight of the carrier; or b) about 40% by weight of the carrierof a liquid oil and about 60% by weight of the carrier of a paraffin wax42-44° C.; and a liquefied or compressed gas propellant; wherein theratio of the carrier to the propellant is from about 100:4 to about100:25; wherein the composition comprises less than 5% foam adjuvant;and wherein upon dispensing the foamable composition from a container,the composition forms a breakable foam that is stable, yet breaks easilyupon application of shear force.
 25. The composition of claim 2, whereinthe active agent is a cosmetic agent.
 26. The composition of claim 1,wherein the liquid oil is selected from a mineral oil, capric/caprylictriglyceride, PPG-15 stearyl ether, isopropyl palmitate, isopropylmyristate, octyldodecanol, and a mixture of two or more thereof.
 27. Thecomposition of claim 26, wherein the liquid oil comprises a mineral oil.28. The composition of claim 27, wherein the mineral oil is a heavymineral oil, a light mineral oil, or a mixture thereof.
 29. Thecomposition of claim 19, wherein the liquid oil is selected from amineral oil, capric/caprylic triglyceride, PPG-15 stearyl ether,isopropyl palmitate, isopropyl myristate, octyldodecanol, and a mixtureof two or more thereof.
 30. The composition of claim 29, wherein theliquid oil comprises a mineral oil.
 31. The composition of claim 24,wherein the liquid oil is selected from a mineral oil, capric/caprylictriglyceride, PPG-15 stearyl ether, isopropyl palmitate, isopropylmyristate, octyldodecanol, and a mixture of two or more thereof.
 32. Thecomposition of claim 31, wherein the liquid oil comprises a mineral oil.33. The composition of claim 1, wherein the ratio of the carrier to thepropellant is from about 100:8 to about 100:12.
 34. The composition ofclaim 19, wherein the ratio of the carrier to the propellant is fromabout 100:8 to about 100:12.
 35. The composition of claim 24, whereinthe ratio of the carrier to the propellant is from about 100:8 to about100:12.
 36. A waterless foamable composition free of surfactant andpolymeric agent comprising: a carrier comprising: a) about 50% to about90% by weight of the carrier of a liquid oil and about 10% to about 50%by weight of the carrier of a paraffin wax that has a melting pointbetween about 47° C. and about 64° C., wherein the total weight of theliquid oil and paraffin wax together is between about 85% and about 100%by weight of the carrier; or b) about 40% by weight of the carrier of aliquid oil and about 60% by weight of the carrier of a paraffin wax thathas a melting point between about 42° C. and about 44° C.; and c) anactive agent; wherein the composition comprises less than 5% foamadjuvant; and wherein, when a liquefied propellant is added to thefoamable composition in an aerosol in an amount effective to achieve anacceptable foam, the composition forms a breakable foam upon dispensingthat is stable, yet breaks easily upon application of shear force. 37.The composition of claim 36, wherein the ratio of the carrier to thepropellant is from about 100:4 to about 100:25.
 38. The composition ofclaim 36, wherein the ratio of the carrier to the propellant is fromabout 100:8 to about 100:12.
 39. The composition of claim 36, whereinthe liquid oil is selected from a mineral oil, capric/caprylictriglyceride, PPG-15 stearyl ether, isopropyl palmitate, isopropylmyristate, octyldodecanol, and a mixture of two or more thereof.
 40. Thecomposition of claim 39, wherein the liquid oil comprises a mineral oil.41. The composition of claim 40, wherein the mineral oil is a heavymineral oil, a light mineral oil, or a mixture thereof.
 42. Thecomposition of claim 36, wherein the paraffin wax is selected from aparaffin wax 58-62° C., a paraffin wax 51-53° C., and a mixture thereof.43. The composition of claim 1, wherein the liquid oil comprises amineral oil, a soybean oil, a coconut oil, a silicone oil or a mixtureof any two or more thereof.
 44. The composition of claim 19, wherein theliquid oil comprises a mineral oil, a soybean oil, a coconut oil, asilicone oil or a mixture of any two or more thereof.
 45. Thecomposition of claim 24, wherein the liquid oil comprises a mineral oil,a soybean oil, a coconut oil, a silicone oil or a mixture of any two ormore thereof.
 46. The composition of claim 36, wherein the liquid oilcomprises a mineral oil, a soybean oil, a coconut oil, a silicone oil ora mixture of any two or more thereof.
 47. The composition of claim 36,wherein the active agent comprises a doxycycline, a minocycline, orboth.
 48. The composition of claim 36, wherein the active agentcomprises a tetracycline.